Related Publications
2576724
IXMHRBF6
skin cancer
1
apa-cv
50
date
desc
1
1
4131
https://labsyspharm.org/wp-content/plugins/zotpress/
%7B%22status%22%3A%22success%22%2C%22updateneeded%22%3Afalse%2C%22instance%22%3Afalse%2C%22meta%22%3A%7B%22request_last%22%3A0%2C%22request_next%22%3A0%2C%22used_cache%22%3Atrue%7D%2C%22data%22%3A%5B%7B%22key%22%3A%228ITYBD4Z%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Zimmerman%20et%20al.%22%2C%22parsedDate%22%3A%222026-02-08%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EZimmerman%2C%20M.%20P.%2C%20Huang%2C%20A.%20C.%2C%20Cox%2C%20E.%20K.%2C%20Al%20Abosy%2C%20R.%2C%20Chong%2C%20W.%20L.%2C%20Bastian%2C%20A.%20G.%2C%20Vietor%2C%20K.%2C%20Choutri%2C%20Y.%2C%20Collier%2C%20J.%2C%20Zhabotynsky%2C%20V.%2C%20Wang%2C%20H.%2C%20Fung%2C%20M.%2C%20Weiss%2C%20S.%20A.%2C%20Robitschek%2C%20E.%20J.%2C%20Lin%2C%20J.-R.%2C%20Vallius%2C%20T.%2C%20Pant%2C%20S.%2C%20Sorger%2C%20P.%20K.%2C%20Hugo%2C%20W.%2C%20%26%23x2026%3B%20Miller%2C%20B.%20C.%20%282026%29.%20%3Ci%3EHarnessing%20Inflammatory%20Monocytes%20to%20Overcome%20Resistance%20to%20Anti-PD-1%20Immunotherapy%3C%5C%2Fi%3E.%20bioRxiv.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.64898%5C%2F2026.02.05.704029%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.64898%5C%2F2026.02.05.704029%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22preprint%22%2C%22title%22%3A%22Harnessing%20Inflammatory%20Monocytes%20to%20Overcome%20Resistance%20to%20Anti-PD-1%20Immunotherapy%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Matthew%20P.%22%2C%22lastName%22%3A%22Zimmerman%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Amy%20C.%22%2C%22lastName%22%3A%22Huang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Emily%20K.%22%2C%22lastName%22%3A%22Cox%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Rose%22%2C%22lastName%22%3A%22Al%20Abosy%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Wan%20Lin%22%2C%22lastName%22%3A%22Chong%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alexander%20G.%22%2C%22lastName%22%3A%22Bastian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Katherine%22%2C%22lastName%22%3A%22Vietor%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yacine%22%2C%22lastName%22%3A%22Choutri%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jenna%22%2C%22lastName%22%3A%22Collier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Vasyl%22%2C%22lastName%22%3A%22Zhabotynsky%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Haiyang%22%2C%22lastName%22%3A%22Wang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Megan%22%2C%22lastName%22%3A%22Fung%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sarah%20A.%22%2C%22lastName%22%3A%22Weiss%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Emily%20J.%22%2C%22lastName%22%3A%22Robitschek%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jia-Ren%22%2C%22lastName%22%3A%22Lin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tuulia%22%2C%22lastName%22%3A%22Vallius%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shishir%22%2C%22lastName%22%3A%22Pant%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20Karl%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Willy%22%2C%22lastName%22%3A%22Hugo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Debattama%20R.%22%2C%22lastName%22%3A%22Sen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22William%20Nicholas%22%2C%22lastName%22%3A%22Haining%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Arlene%20H.%22%2C%22lastName%22%3A%22Sharpe%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Brian%20C.%22%2C%22lastName%22%3A%22Miller%22%7D%5D%2C%22abstractNote%22%3A%22BACKGROUND%3A%20Resistance%20to%20immune%20checkpoint%20inhibitors%20represents%20a%20major%20therapeutic%20challenge%2C%20as%20less%20than%2050%25%20of%20patients%20with%20melanoma%20achieve%20long-term%20response%20to%20immune%20checkpoint%20inhibitor%20therapy.%20One%20mechanism%20of%20acquired%20resistance%20involves%20somatic%20mutations%2C%20such%20as%20loss%20of%20beta-2%20microglobulin%20%28B2m%29%2C%20that%20enable%20tumor%20cells%20to%20evade%20T%20cell-mediated%20killing.%5CnMETHODS%3A%20This%20study%20used%20single-cell%20RNA-seq%2C%20flow%20cytometry%2C%20and%20ex%20vivo%20functional%20assays%20to%20characterize%20tumor-infiltrating%20immune%20cells%20in%20antigen%20presentation-deficient%20tumors.%20Tumor-bearing%20mice%20were%20treated%20with%20anti-PD-1%20or%20CD40%20agonist%20antibodies%20and%20cell%20depletion%20or%20cytokine%20blocking%20antibodies%20to%20define%20mechanisms%20of%20action.%20Analysis%20of%20published%20human%20RNA-seq%20datasets%20was%20performed%20to%20dissect%20the%20contributions%20of%20inflammatory%20monocytes%20to%20patient%20outcomes.%5CnRESULTS%3A%20We%20found%20an%20increase%20in%20immunosuppressive%20macrophages%20in%20B2m-null%20tumors.%20We%20hypothesized%20that%20repolarizing%20myeloid%20cells%20may%20restore%20control%20of%20tumor%20growth.%20Treatment%20with%20CD40%20agonist%20antibody%2C%20which%20promotes%20differentiation%20of%20monocytes%20and%20macrophages%20towards%20a%20proinflammatory%20phenotype%2C%20reduced%20tumor%20growth%20and%20improved%20survival%20in%20B2m-null%20melanoma%20and%20colorectal%20cancer%20models.%20Unexpectedly%2C%20both%20CD8%2B%20T%20cells%20and%20NK%20cells%2C%20but%20not%20CD4%2B%20T%20cells%2C%20were%20required%20for%20the%20efficacy%20of%20CD40%20agonist%2C%20even%20though%20CD8%2B%20T%20cells%20cannot%20directly%20recognize%20antigen%20presentation-deficient%20tumor%20cells.%20Instead%2C%20these%20lymphocytes%20control%20tumor%20growth%20via%20secretion%20of%20IFN%5Cu03b3%2C%20as%20depletion%20of%20IFN%5Cu03b3%20inhibited%20the%20therapeutic%20effect%20of%20CD40%20agonist.%20IFN%5Cu03b3%20receptor%20%28Ifngr1%29%20expression%20was%20required%20on%20host%20cells%2C%20not%20tumor%20cells%2C%20for%20CD40%20agonist-mediated%20tumor%20control.%20Single-cell%20analysis%20identified%20a%20distinct%20population%20of%20inflammatory%20monocytes%20that%20were%20enriched%20for%20an%20IFN%5Cu03b3%20response%20signature%20in%20CD40%20agonist-treated%20tumors%2C%20suggesting%20that%20these%20cells%20may%20be%20important%20for%20tumor%20control.%20Analysis%20of%20human%20bulk%20and%20single-cell%20RNA-seq%20datasets%20demonstrated%20that%20an%20inflammatory%20monocyte%20signature%20derived%20from%20our%20data%20was%20associated%20with%20improved%20patient%20outcomes%20and%20response%20to%20immune%20checkpoint%20inhibitors.%5CnCONCLUSIONS%3A%20These%20data%20demonstrate%20that%20CD8%2B%20T%20cells%20contribute%20to%20tumor%20control%20even%20in%20the%20absence%20of%20direct%20antigen%20presentation%20by%20tumor%20cells.%20More%20broadly%2C%20our%20work%20suggests%20that%20strategies%20to%20activate%20the%20effector%20functions%20of%20inflammatory%20monocytes%20may%20limit%20tumor%20growth%20and%20overcome%20acquired%20resistance%20to%20immune%20checkpoint%20inhibitors.%22%2C%22genre%22%3A%22%22%2C%22repository%22%3A%22bioRxiv%22%2C%22archiveID%22%3A%22%22%2C%22date%22%3A%222026-02-08%22%2C%22DOI%22%3A%2210.64898%5C%2F2026.02.05.704029%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-02-20T22%3A03%3A58Z%22%7D%7D%2C%7B%22key%22%3A%22F5M4P7YL%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Weems%20et%20al.%22%2C%22parsedDate%22%3A%222026-01-05%22%2C%22numChildren%22%3A0%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EWeems%2C%20A.%20D.%2C%20Islam%2C%20M.%20T.%2C%20Borges%2C%20H.%2C%20Yapp%2C%20C.%2C%20Perez-Castro%2C%20L.%2C%20Nogueira%2C%20P.%2C%20Lin%2C%20J.%2C%20Maliga%2C%20Z.%2C%20Lewis%2C%20A.%20J.%2C%20Kutter%2C%20C.%2C%20Mannino%2C%20M.%2C%20Vallius%2C%20T.%2C%20Santagata%2C%20S.%2C%20Sorger%2C%20P.%20K.%2C%20Conacci-Sorrell%2C%20M.%2C%20Dean%2C%20K.%20M.%2C%20%26amp%3B%20Danuser%2C%20G.%20M.%20%282026%29.%20%3Ci%3EIn%20vivo%20evidence%20for%20bleb-induced%20survival%20signaling%20in%20metastatic%20melanoma%3C%5C%2Fi%3E.%20Cancer%20Biology.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.64898%5C%2F2026.01.05.697601%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.64898%5C%2F2026.01.05.697601%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22preprint%22%2C%22title%22%3A%22In%20vivo%20evidence%20for%20bleb-induced%20survival%20signaling%20in%20metastatic%20melanoma%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Andrew%20D.%22%2C%22lastName%22%3A%22Weems%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Md%20Torikul%22%2C%22lastName%22%3A%22Islam%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hazel%22%2C%22lastName%22%3A%22Borges%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Clarence%22%2C%22lastName%22%3A%22Yapp%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lizbeth%22%2C%22lastName%22%3A%22Perez-Castro%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Pedro%22%2C%22lastName%22%3A%22Nogueira%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jinlong%22%2C%22lastName%22%3A%22Lin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zoltan%22%2C%22lastName%22%3A%22Maliga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alecxander%20J%22%2C%22lastName%22%3A%22Lewis%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Camille%22%2C%22lastName%22%3A%22Kutter%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mark%22%2C%22lastName%22%3A%22Mannino%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tuulia%22%2C%22lastName%22%3A%22Vallius%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sandro%22%2C%22lastName%22%3A%22Santagata%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20Karl%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Maralice%22%2C%22lastName%22%3A%22Conacci-Sorrell%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kevin%20M.%22%2C%22lastName%22%3A%22Dean%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gaudenz%20M.%22%2C%22lastName%22%3A%22Danuser%22%7D%5D%2C%22abstractNote%22%3A%22Bleb%20signaling%20is%20a%20cellular%20process%20in%20which%20pressure-driven%20plasma%20membrane%20protrusions%20generate%20localized%20micron-scale%20membrane%20curvature%20that%20recruits%20cytosolic%20septin%20complexes%2C%20assembling%20signaling%20hubs%20that%20promote%20cell%20survival.%20Our%20prior%20work%20showed%20that%20this%20morphology-encoded%20signaling%20pathway%20is%20necessary%20to%20sustain%20anchorage-independent%20survival%20of%20BRAF%20and%20NRAS%20mutant%20melanoma%20cells%20in%20vitro.%20However%2C%20whether%20bleb-induced%20signaling%20occurs%20in%20vivo%20and%20contributes%20to%20cancer%20progression%20is%20unclear.%20Here%2C%20we%20develop%20complementary%20in%20vivo%20and%20ex%20vivo%20assays%20spanning%20human%20patient%20samples%20and%20mouse%20xenograft%20models%20to%20mechanistically%20interrogate%20bleb%20signaling%20directly%20in%20physiologic%20contexts.%20We%20observe%20that%20bleb-associated%20septin%20hubs%20are%20exclusively%20formed%20in%20poorly%20adherent%20amoeboid%20tumor%20cells%20at%20the%20invasive%20margin%2C%20within%20malignant%20effusions%2C%20and%20at%20distant%20metastatic%20sites%2C%20while%20well-adhered%20cells%20in%20the%20tumor%20interior%20show%20no%20signs%20of%20septin%20hub%20formation.%20Accordingly%2C%20pharmacological%20pathway%20disruption%20specifically%20kills%20disseminated%20tumor%20cells%20within%20these%20low-adhesion%20microenvironments%20while%20having%20no%20appreciable%20effect%20on%20adhered%20cells%20in%20the%20tumor%20interior%2C%20resulting%20in%20reduced%20metastatic%20burden%20and%20delayed%20disease%20recurrence%20in%20vivo.%20This%20work%20confirms%20septin-mediated%20bleb%20signaling%20as%20a%20previously%20unrecognized%20vulnerability%20of%20disseminated%20cancer%20cells%20and%20demonstrates%20that%20this%20morphology-encoded%20pathway%20operates%20in%20vivo%20to%20support%20disease%20progression%2C%20preserving%20cancer%20cell%20viability%20under%20conditions%20in%20which%20cell%20survival%20signals%20from%20the%20environment%20are%20muted.%20These%20findings%20suggest%20novel%20opportunities%20to%20target%20survival%20signaling%20in%20micrometastatic%20disseminated%20cancer%20cells.%22%2C%22genre%22%3A%22%22%2C%22repository%22%3A%22Cancer%20Biology%22%2C%22archiveID%22%3A%22%22%2C%22date%22%3A%222026-01-05%22%2C%22DOI%22%3A%2210.64898%5C%2F2026.01.05.697601%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22http%3A%5C%2F%5C%2Fbiorxiv.org%5C%2Flookup%5C%2Fdoi%5C%2F10.64898%5C%2F2026.01.05.697601%22%2C%22language%22%3A%22en%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-02-19T20%3A03%3A13Z%22%7D%7D%2C%7B%22key%22%3A%22B99338KT%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Rapisuwon%20et%20al.%22%2C%22parsedDate%22%3A%222026-01%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ERapisuwon%2C%20S.%2C%20Slingluff%2C%20C.%20L.%2C%20Wargo%2C%20J.%20A.%2C%20Sullivan%2C%20R.%20J.%2C%20Izar%2C%20B.%2C%20Lin%2C%20J.-R.%2C%20Mauldin%2C%20I.%20S.%2C%20Olson%2C%20W.%20C.%2C%20Tran%2C%20C.%20A.%2C%20Schwartzman%2C%20G.%20H.%2C%20Gibney%2C%20G.%20T.%2C%20Al-Refaie%2C%20W.%2C%20%26amp%3B%20Atkins%2C%20M.%20B.%20%282026%29.%20Effects%20of%20Vemurafenib%20%26%23xB1%3B%20Cobimetinib%20on%20Intratumoral%20and%20Host%20Immunity%20in%20Patients%20With%20BRAFV600%20Mutant%20Melanoma%3A%20Implications%20for%20Combination%20With%20Immunotherapy.%20%3Ci%3ECancer%20Medicine%3C%5C%2Fi%3E%2C%20%3Ci%3E15%3C%5C%2Fi%3E%281%29%2C%20e71526.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1002%5C%2Fcam4.71526%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1002%5C%2Fcam4.71526%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Effects%20of%20Vemurafenib%20%5Cu00b1%20Cobimetinib%20on%20Intratumoral%20and%20Host%20Immunity%20in%20Patients%20With%20BRAFV600%20Mutant%20Melanoma%3A%20Implications%20for%20Combination%20With%20Immunotherapy%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Suthee%22%2C%22lastName%22%3A%22Rapisuwon%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Craig%20L.%22%2C%22lastName%22%3A%22Slingluff%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jennifer%20A.%22%2C%22lastName%22%3A%22Wargo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ryan%20J.%22%2C%22lastName%22%3A%22Sullivan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benjamin%22%2C%22lastName%22%3A%22Izar%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jia-Ren%22%2C%22lastName%22%3A%22Lin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ileana%20S.%22%2C%22lastName%22%3A%22Mauldin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Walter%20C.%22%2C%22lastName%22%3A%22Olson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%20A.%22%2C%22lastName%22%3A%22Tran%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gabrielle%20H.%22%2C%22lastName%22%3A%22Schwartzman%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Geoffrey%20T.%22%2C%22lastName%22%3A%22Gibney%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Waddah%22%2C%22lastName%22%3A%22Al-Refaie%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Michael%20B.%22%2C%22lastName%22%3A%22Atkins%22%7D%5D%2C%22abstractNote%22%3A%22BACKGROUND%3A%20Prior%20studies%20in%20patients%20with%20BRAF-mutant%20melanoma%20have%20shown%20increased%20density%20of%20tumor%20infiltrating%20lymphocytes%20%28TIL%29%20after%202%5Cu2009weeks%20of%20BRAF%20%28BRAFi%29%5Cu2009%5Cu00b1%5Cu2009MEK%20inhibition%20%28MEKi%29%2C%20but%20did%20not%20characterize%20the%20functional%20state%20or%20clonal%20diversity%20of%20TIL%20over%20time.%20We%20evaluated%20sequential%20tumor%20biopsies%20during%20therapy%20to%20test%20the%20hypotheses%20that%20BRAF%5C%2FMEKi%20would%20increase%20TIL%20to%20day%2029%2C%20with%20increases%20in%20IFN%5Cu03b3%20signatures%20and%20T-cell%20homing%20receptor%20ligands%20and%20expansion%20of%20functional%20intratumoral%20tumor-reactive%20CD8%20T-cells%20and%20TIL%20clonality%20in%20the%20tumor%20microenvironment.%5CnMETHODS%3A%20Subjects%20with%20biopsy-accessible%20BRAF-mutant%20advanced%20melanoma%20received%20vemurafenib%2B%5C%2F-cobimetinib.%20Tumor%20biopsies%20were%20obtained%20at%20baseline%20and%20days%208%2C%2015%2C%20and%2029%20on%20therapy.%20Tumors%20were%20analyzed%20by%20quantitative%20immunofluorescence%20%28QIF%29%2C%20NanoString%2C%20and%20TCRseq.%5CnRESULTS%3A%20Five%20patients%20were%20enrolled.%20All%20had%20an%20initial%20tumor%20response%20followed%20by%20subsequent%20progression.%20In%20four%20patients%2C%20both%20CD8%2B%20and%20CD4%2B%20TIL%20density%20increased%20by%20day%208%20or%2015%20per%20QIF%20and%20continued%20to%20increase%20at%20day%2029%20in%20two.%20Gene%20expression%20data%20showed%20upregulation%20of%20genes%5C%2Fpathways%20associated%20with%20immunologic%20rejection%20of%20cancer%2C%20including%20Class%20I%20and%20II%20MHC%20expression%2C%20antigen%20processing%5C%2Fpresentation%2C%20and%20critical%20T-cell%20attracting%20chemokines.%20TCRv%5Cu03b2%20clonal%20expansion%20was%20observed%20in%203%20patients%2C%20but%20most%20diminished%20after%20day%2015.%5CnCONCLUSIONS%3A%20Data%20from%20this%20study%20provides%20provocative%20evidence%20that%2C%20while%20BRAF%2B%5C%2F-MEK%20inhibitor%20therapy%20produces%20an%20increase%20in%20overall%20and%20clonal%20T%20cell%20infiltrates%2C%20there%20is%20limited%20evidence%20for%20generation%20of%20new%20or%20persistent%20tumor%20immunity.%20Thus%2C%20BRAFi%5C%2FMEKi%20therapy%20may%20enable%20tumor-reactive%20T%20cells%20to%20infiltrate%20tumors%20but%20tumor%20control%20does%20not%20appear%20to%20depend%20on%20priming%20new%20immune%20responses.%22%2C%22date%22%3A%222026-01%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1002%5C%2Fcam4.71526%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2241514118%22%2C%22PMCID%22%3A%22PMC12789045%22%2C%22ISSN%22%3A%222045-7634%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-02-19T20%3A10%3A01Z%22%7D%7D%2C%7B%22key%22%3A%22PT8X8BDH%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Shi%20et%20al.%22%2C%22parsedDate%22%3A%222025-12-15%22%2C%22numChildren%22%3A0%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EShi%2C%20Y.%2C%20Maliga%2C%20Z.%2C%20Vallius%2C%20T.%2C%20Pant%2C%20S.%20M.%2C%20Pelletier%2C%20R.%2C%20Kobs%2C%20B.%2C%20Solanky%2C%20P.%2C%20He%2C%20Y.%2C%20Van%20Allen%2C%20E.%2C%20Santagata%2C%20S.%2C%20Ott%2C%20P.%2C%20Lian%2C%20C.%20G.%2C%20Buchbinder%2C%20E.%2C%20Liu%2C%20D.%2C%20%26amp%3B%20Sorger%2C%20P.%20K.%20%282025%29.%20%3Ci%3EMechanisms%20of%20tumor%20persistence%20in%20metastatic%20melanoma%20following%20successful%20immunotherapy%3C%5C%2Fi%3E.%20bioRxiv.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.64898%5C%2F2025.12.11.692633%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.64898%5C%2F2025.12.11.692633%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22preprint%22%2C%22title%22%3A%22Mechanisms%20of%20tumor%20persistence%20in%20metastatic%20melanoma%20following%20successful%20immunotherapy%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yingxiao%22%2C%22lastName%22%3A%22Shi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zoltan%22%2C%22lastName%22%3A%22Maliga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tuulia%22%2C%22lastName%22%3A%22Vallius%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shishir%20M%22%2C%22lastName%22%3A%22Pant%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Roxanne%22%2C%22lastName%22%3A%22Pelletier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Brigette%22%2C%22lastName%22%3A%22Kobs%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Priyanka%22%2C%22lastName%22%3A%22Solanky%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yiwen%22%2C%22lastName%22%3A%22He%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Eliezer%22%2C%22lastName%22%3A%22Van%20Allen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sandro%22%2C%22lastName%22%3A%22Santagata%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Patrick%22%2C%22lastName%22%3A%22Ott%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%20G%22%2C%22lastName%22%3A%22Lian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elizabeth%22%2C%22lastName%22%3A%22Buchbinder%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20Karl%22%2C%22lastName%22%3A%22Sorger%22%7D%5D%2C%22abstractNote%22%3A%22Persistent%20stable%20lesions%20represent%20a%20common%20but%20ambiguous%20outcome%20in%20melanoma%20patients%20receiving%20immune%20checkpoint%20inhibitors%20%28ICIs%29.%20However%2C%20these%20lesions%20are%20infrequently%20removed%20and%20poorly%20characterized.%20Here%2C%20we%20perform%20in-depth%20multi-omics%20spatial%20profiling%20on%20persistent%20stable%20lesions%20from%20six%20ICI-treated%20patients.%20In%20one%2C%20the%20proportion%20of%20viable%20and%20proliferating%20tumor%20cells%20was%20similar%20to%20that%20of%20site-matched%20tumors%20from%20patients%20progressing%20during%20ICI.%20Extensive%20infiltration%20with%20cytotoxic%20T%20cells%20and%20a%20high%20level%20of%20programmed%20cell%20death%20were%20also%20observed.%20Some%20quiescent%20cancer%20cells%20were%20present%2C%20but%20this%20was%20not%20the%20dominant%20tumor%20state.%20A%20second%20stable%20lesion%2C%20while%20pathologically%20negative%2C%20also%20contained%20proliferative%20tumor%20nests%20with%20proximate%20immune%20cells.%20These%20findings%20provide%20evidence%20in%20patients%20for%20extended%20tumor%20mass%20dormancy%20in%20which%20cell%20death%20balances%20ongoing%20proliferation%20and%20further%20demonstrate%20that%20persistent%20stable%20lesions%20can%20be%20reservoirs%20of%20viable%20tumor%20cells%20with%20implications%20for%20clinical%20monitoring%20and%20management.%22%2C%22genre%22%3A%22%22%2C%22repository%22%3A%22bioRxiv%22%2C%22archiveID%22%3A%22%22%2C%22date%22%3A%222025-12-15%22%2C%22DOI%22%3A%2210.64898%5C%2F2025.12.11.692633%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22http%3A%5C%2F%5C%2Fbiorxiv.org%5C%2Flookup%5C%2Fdoi%5C%2F10.64898%5C%2F2025.12.11.692633%22%2C%22language%22%3A%22en%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-02-19T20%3A36%3A06Z%22%7D%7D%2C%7B%22key%22%3A%22ITFAJGY2%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Knight%20et%20al.%22%2C%22parsedDate%22%3A%222025-11-04%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EKnight%2C%20A.%20D.%2C%20Robitschek%2C%20E.%20J.%2C%20Lin%2C%20J.-R.%2C%20Frederick%2C%20D.%20T.%2C%20Shi%2C%20A.%2C%20Larque%2C%20A.%20B.%2C%20Miao%2C%20B.%2C%20Raghavan%2C%20R.%20S.%2C%20Sharova%2C%20T.%2C%20Shin%2C%20J.%20H.%2C%20Sorger%2C%20P.%2C%20Kellis%2C%20M.%2C%20Flaherty%2C%20K.%20T.%2C%20Hacohen%2C%20N.%2C%20Boland%2C%20G.%20M.%2C%20Chebib%2C%20I.%2C%20Liu%2C%20D.%2C%20Sullivan%2C%20R.%20J.%2C%20%26amp%3B%20Mehta%2C%20A.%20%282025%29.%20%3Ci%3EMelanoma%20to%20rhabdomyosarcoma%20plasticity%20in%20the%20setting%20of%20immunotherapy%3C%5C%2Fi%3E.%20medRxiv.%20medRxiv.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1101%5C%2F2025.10.31.25338685%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1101%5C%2F2025.10.31.25338685%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22preprint%22%2C%22title%22%3A%22Melanoma%20to%20rhabdomyosarcoma%20plasticity%20in%20the%20setting%20of%20immunotherapy%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Andrew%20D.%22%2C%22lastName%22%3A%22Knight%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Emily%20J.%22%2C%22lastName%22%3A%22Robitschek%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jia-Ren%22%2C%22lastName%22%3A%22Lin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Dennie%20T.%22%2C%22lastName%22%3A%22Frederick%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alvin%22%2C%22lastName%22%3A%22Shi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ana%20B.%22%2C%22lastName%22%3A%22Larque%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benchun%22%2C%22lastName%22%3A%22Miao%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Rumya%20S.%22%2C%22lastName%22%3A%22Raghavan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tatyana%22%2C%22lastName%22%3A%22Sharova%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22John%20H.%22%2C%22lastName%22%3A%22Shin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Manolis%22%2C%22lastName%22%3A%22Kellis%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Keith%20T.%22%2C%22lastName%22%3A%22Flaherty%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nir%22%2C%22lastName%22%3A%22Hacohen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Genevieve%20M.%22%2C%22lastName%22%3A%22Boland%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ivan%22%2C%22lastName%22%3A%22Chebib%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ryan%20J.%22%2C%22lastName%22%3A%22Sullivan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Arnav%22%2C%22lastName%22%3A%22Mehta%22%7D%5D%2C%22abstractNote%22%3A%22Acquired%20resistance%20to%20immune%20checkpoint%20inhibitors%20%28ICIs%29%20remains%20a%20significant%20challenge%20in%20the%20treatment%20of%20metastatic%20melanoma.%20Phenotypic%20plasticity%2C%20such%20as%20dedifferentiation%20and%20transdifferentiation%2C%20is%20an%20increasingly%20recognized%20mechanism%20for%20treatment%20resistance.%20We%20present%20a%20case%20of%20a%20man%20in%20his%2070s%20with%20metastatic%20melanoma%20who%20experienced%20progression%20through%20sequential%20treatments%20including%20pembrolizumab%20in%20combination%20with%20the%20HDAC%20inhibitor%20entinostat%2C%20and%20ipilimumab.%20During%20treatment%20a%20histologically%20distinct%20pleomorphic%20rhabdomyosarcoma%20%28RMS%29%20emerged%20at%20metastatic%20sites.%20Longitudinally%20acquired%20tumor%20samples%20representing%20both%20phenotypes%20were%20analyzed%20using%20whole-exome%20sequencing%20%28WES%29%2C%20RNA%20sequencing%20%28RNA-seq%29%20and%20high-plex%20tissue%20imaging%20%28spatial%20proteomics%29.%20WES%20revealed%20driver%20mutations%20%28e.g.%20NRAS%2C%20NF1%29%20and%20loss-of-heterozygosity%20%28LOH%29%20shared%20between%20phenotypes%20indicating%20a%20common%20ancestral%20clone.%20Phylogenetic%20analysis%20demonstrated%20an%20early%20divergence%20of%20the%20phenotypes%2C%20with%20each%20later%20acquiring%20unique%20mutations.%20RNA-seq%20showed%20mutually%20exclusive%20expression%20of%20lineage-specific%20markers%20as%20well%20as%20epithelial-mesenchymal%20transition%20and%20myogenic%20gene%20set%20enrichment%20in%20the%20RMS%20samples.%20High-plex%20imaging%20identified%20distinct%20tumor%20microenvironments%2C%20with%20RMS%20lesions%20enriched%20in%20CD163%20%2B%20macrophages.%5CnSTATEMENT%20OF%20SIGNIFICANCE%3A%20Transdifferentiation%20has%20been%20observed%20in%20a%20wide%20range%20of%20malignancies%2C%20but%20the%20molecular%20mechanisms%20of%20this%20phenomenon%20are%20poorly%20understood.%20This%20case%20provides%20the%20first%20molecularly%20validated%20example%20of%20melanoma%20to%20rhabdomyosarcoma%20transdifferentiation%20presenting%20as%20spatially%20segregated%20metastatic%20lesions%20with%20distinct%2C%20unmixed%20histologies%20and%20illustrates%20a%20mechanism%20of%20resistance%20to%20immunotherapy%20driven%20by%20phenotypic%20plasticity.%22%2C%22genre%22%3A%22%22%2C%22repository%22%3A%22medRxiv%22%2C%22archiveID%22%3A%22%22%2C%22date%22%3A%222025-11-04%22%2C%22DOI%22%3A%2210.1101%5C%2F2025.10.31.25338685%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-02-19T21%3A24%3A55Z%22%7D%7D%2C%7B%22key%22%3A%22FT8PJJK7%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Ludin%20et%20al.%22%2C%22parsedDate%22%3A%222025-10-17%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ELudin%2C%20A.%2C%20Stirtz%2C%20G.%20L.%2C%20Tal%2C%20A.%2C%20Nirmal%2C%20A.%20J.%2C%20Pfaff%2C%20K.%20L.%2C%20Manos%2C%20M.%2C%20Besson%2C%20N.%2C%20Eskndir%2C%20N.%2C%20Porter%2C%20B.%2C%20Jones%2C%20S.%20M.%2C%20Faulkner%2C%20H.%20M.%2C%20Gong%2C%20Q.%2C%20Liu%2C%20S.%2C%20Barrera%2C%20I.%2C%20Wu%2C%20L.%2C%20Pessoa%20Rodrigues%2C%20C.%2C%20Sahu%2C%20A.%2C%20Jerison%2C%20E.%2C%20Alessi%2C%20J.%20V.%2C%20%26%23x2026%3B%20Zon%2C%20L.%20I.%20%282025%29.%20CRATER%20tumor%20niches%20facilitate%20CD8%2B%20T%20cell%20engagement%20and%20correspond%20with%20immunotherapy%20success.%20%3Ci%3ECell%3C%5C%2Fi%3E%2C%20S0092-8674%2825%2901089-X.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.cell.2025.09.021%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.cell.2025.09.021%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22CRATER%20tumor%20niches%20facilitate%20CD8%2B%20T%20cell%20engagement%20and%20correspond%20with%20immunotherapy%20success%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Aya%22%2C%22lastName%22%3A%22Ludin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Georgia%20L.%22%2C%22lastName%22%3A%22Stirtz%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Asaf%22%2C%22lastName%22%3A%22Tal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ajit%20J.%22%2C%22lastName%22%3A%22Nirmal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kathleen%20L.%22%2C%22lastName%22%3A%22Pfaff%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Michael%22%2C%22lastName%22%3A%22Manos%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Naomi%22%2C%22lastName%22%3A%22Besson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nebiyat%22%2C%22lastName%22%3A%22Eskndir%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Billie%22%2C%22lastName%22%3A%22Porter%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Stephanie%20M.%22%2C%22lastName%22%3A%22Jones%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hannah%20M.%22%2C%22lastName%22%3A%22Faulkner%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Qiyu%22%2C%22lastName%22%3A%22Gong%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sophia%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Irving%22%2C%22lastName%22%3A%22Barrera%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lijian%22%2C%22lastName%22%3A%22Wu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Cecilia%22%2C%22lastName%22%3A%22Pessoa%20Rodrigues%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Aditi%22%2C%22lastName%22%3A%22Sahu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elizabeth%22%2C%22lastName%22%3A%22Jerison%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Joao%20V.%22%2C%22lastName%22%3A%22Alessi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Biagio%22%2C%22lastName%22%3A%22Ricciuti%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Douglas%20S.%22%2C%22lastName%22%3A%22Richardson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jodi%20D.%22%2C%22lastName%22%3A%22Weiss%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hadley%20M.%22%2C%22lastName%22%3A%22Moreau%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Meredith%20E.%22%2C%22lastName%22%3A%22Stanhope%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alexander%20B.%22%2C%22lastName%22%3A%22Afeyan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22James%22%2C%22lastName%22%3A%22Sefton%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Wyatt%20D.%22%2C%22lastName%22%3A%22McCall%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Emily%22%2C%22lastName%22%3A%22Formato%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Song%22%2C%22lastName%22%3A%22Yang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yi%22%2C%22lastName%22%3A%22Zhou%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%20P.%22%2C%22lastName%22%3A%22Hoytema%20van%20Konijnenburg%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hannah%20L.%22%2C%22lastName%22%3A%22Cole%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Miguel%22%2C%22lastName%22%3A%22Cordova%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Liang%22%2C%22lastName%22%3A%22Deng%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Milind%22%2C%22lastName%22%3A%22Rajadhyaksha%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Stephen%20R.%22%2C%22lastName%22%3A%22Quake%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mark%20M.%22%2C%22lastName%22%3A%22Awad%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Fei%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kai%20W.%22%2C%22lastName%22%3A%22Wucherpfennig%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22F.%20Stephen%22%2C%22lastName%22%3A%22Hodi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Scott%20J.%22%2C%22lastName%22%3A%22Rodig%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22George%20F.%22%2C%22lastName%22%3A%22Murphy%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Leonard%20I.%22%2C%22lastName%22%3A%22Zon%22%7D%5D%2C%22abstractNote%22%3A%22T%20cell-mediated%20tumor%20killing%20underlies%20immunotherapy%20success.%20Here%2C%20we%20used%20long-term%20in%20vivo%20imaging%20and%20high-resolution%20spatial%20transcriptomics%20of%20zebrafish%20endogenous%20melanoma%2C%20as%20well%20as%20multiplex%20imaging%20of%20human%20melanoma%2C%20to%20identify%20domains%20facilitating%20the%20immune%20response%20during%20immunotherapy.%20We%20identified%20cancer%20regions%20of%20antigen%20presentation%20and%20T%20cell%20engagement%20and%20retention%20%28CRATERs%29%20as%20pockets%20at%20the%20stroma-melanocyte%20boundaries%20of%20zebrafish%20and%20human%20melanoma.%20CRATERs%20are%20rich%20in%20antigen-recognition%20molecules%2C%20harboring%20the%20highest%20density%20of%20CD8%2B%20T%20cells%20in%20tumors.%20In%20zebrafish%2C%20CD8%2B%20T%20cells%20formed%20prolonged%20interactions%20with%20melanoma%20cells%20within%20CRATERs%2C%20characteristic%20of%20antigen%20recognition.%20Following%20immunostimulatory%20treatment%2C%20CRATERs%20expanded%2C%20becoming%20the%20major%20sites%20of%20activated%20CD8%2B%20T%20cell%20accumulation%20and%20tumor%20killing.%20In%20humans%2C%20elevation%20in%20CRATER%20density%20in%20biopsies%20following%20immune%20checkpoint%20blockade%20%28ICB%29%20therapy%20correlated%20with%20a%20clinical%20response%20to%20therapy.%20CRATERs%20are%20structures%20that%20show%20active%20tumor%20killing%20and%20may%20be%20useful%20as%20a%20diagnostic%20indicator%20for%20immunotherapy%20success.%22%2C%22date%22%3A%222025-10-17%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1016%5C%2Fj.cell.2025.09.021%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2241109214%22%2C%22PMCID%22%3A%22%22%2C%22ISSN%22%3A%221097-4172%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-02-20T16%3A53%3A45Z%22%7D%7D%2C%7B%22key%22%3A%228Y2Y3GNJ%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Tarantino%20et%20al.%22%2C%22parsedDate%22%3A%222025-10-02%22%2C%22numChildren%22%3A0%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ETarantino%2C%20G.%2C%20Zaremba%2C%20A.%2C%20Vallius%2C%20T.%2C%20Woodnorth%2C%20M.%2C%20Hua%2C%20Y.%2C%20Pelletier%2C%20R.%2C%20Lopez%20Leon%2C%20M.%2C%20Shi%2C%20Y.%2C%20Maliga%2C%20Z.%2C%20Makhzami%2C%20S.%2C%20Aprati%2C%20T.%20J.%2C%20Karlas%2C%20B.%2C%20Glutsch%2C%20V.%2C%20Schilling%2C%20B.%2C%20Hassel%2C%20J.%2C%20Berking%2C%20C.%2C%20Utikal%2C%20J.%2C%20Meier%2C%20F.%2C%20Meiss%2C%20F.%2C%20%26%23x2026%3B%20Schadendorf%2C%20D.%20%282025%29.%20%3Ci%3EMultiomic%20profiling%20of%20a%20unique%20in-transit%20melanoma%20cohort%20identifies%20melanoma%20differentiation%20as%20predictor%20of%20tumor%20progression%20and%20therapy%20response%3C%5C%2Fi%3E.%20bioRxiv.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1101%5C%2F2025.10.01.679282%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1101%5C%2F2025.10.01.679282%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22preprint%22%2C%22title%22%3A%22Multiomic%20profiling%20of%20a%20unique%20in-transit%20melanoma%20cohort%20identifies%20melanoma%20differentiation%20as%20predictor%20of%20tumor%20progression%20and%20therapy%20response%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Giuseppe%22%2C%22lastName%22%3A%22Tarantino%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Anne%22%2C%22lastName%22%3A%22Zaremba%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tuulia%22%2C%22lastName%22%3A%22Vallius%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mark%22%2C%22lastName%22%3A%22Woodnorth%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yichao%22%2C%22lastName%22%3A%22Hua%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Roxanne%22%2C%22lastName%22%3A%22Pelletier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mariana%22%2C%22lastName%22%3A%22Lopez%20Leon%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yingxiao%22%2C%22lastName%22%3A%22Shi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zoltan%22%2C%22lastName%22%3A%22Maliga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Samira%22%2C%22lastName%22%3A%22Makhzami%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tyler%20J%22%2C%22lastName%22%3A%22Aprati%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bojan%22%2C%22lastName%22%3A%22Karlas%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Valerie%22%2C%22lastName%22%3A%22Glutsch%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bastian%22%2C%22lastName%22%3A%22Schilling%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jessica%22%2C%22lastName%22%3A%22Hassel%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Carola%22%2C%22lastName%22%3A%22Berking%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jochen%22%2C%22lastName%22%3A%22Utikal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Friedegund%22%2C%22lastName%22%3A%22Meier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Frank%22%2C%22lastName%22%3A%22Meiss%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lucie%22%2C%22lastName%22%3A%22Heinzerling%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Katharina%22%2C%22lastName%22%3A%22Kahler%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jiajia%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lisa%22%2C%22lastName%22%3A%22Zimmer%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Antje%22%2C%22lastName%22%3A%22Sucker%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elisabeth%22%2C%22lastName%22%3A%22Livingstone%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Eva%22%2C%22lastName%22%3A%22Hadaschik%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%22%2C%22lastName%22%3A%22Lian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22George%22%2C%22lastName%22%3A%22Murphy%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yevgeniy%20R%22%2C%22lastName%22%3A%22Semenov%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Genevieve%20M%22%2C%22lastName%22%3A%22Boland%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Florian%22%2C%22lastName%22%3A%22Rambow%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Dirk%22%2C%22lastName%22%3A%22Schadendorf%22%7D%5D%2C%22abstractNote%22%3A%22Melanoma%20patients%20with%20in-transit%20metastasis%20%28ITM%29%2C%20a%20stage%20of%20disease%20where%20melanoma%20has%20metastasized%20to%20sites%20in%20between%20the%20primary%20lesion%20and%20draining%20lymph%20node%2C%20vary%20significantly%20in%20their%20clinical%20outcomes%2C%20but%20the%20biology%20driving%20differential%20outcomes%20in%20ITM%20is%20poorly%20understood.%20To%20elucidate%20the%20mechanisms%20of%20differential%20outcomes%2C%20we%20utilized%20multimodal%20molecular%20profiling%20%28WES%2C%20RNA-seq%2C%20highly%20multiplexed%20immunofluorescence%2C%20spatial%20transcriptomics%29%20in%201%29%20evolutionary%20analysis%20of%20longitudinal%20tumor%20samples%20and%202%29%20identifying%20prognostic%20tumor%20intrinsic%20and%20microenvironmental%20features%20in%20a%20unique%20cohort%20of%20patients%20with%20unresectable%20ITM.%20Among%20other%20findings%2C%20we%20observed%20a%20persistent%20dedifferentiated%20AXL%5Cu207a%5C%2FNGFR%5Cu207a%20clonal%20lineage%20pre-existing%20and%20following%20immune%20checkpoint%20blockade%20in%20in-transit%20and%20distant%20metastases.%20Concordantly%2C%20we%20found%20that%20low%20pigmentation%20and%20high%20T%20cell%20exhaustion%20signatures%20were%20independently%20associated%20with%20distant%20progression.%20Our%20findings%20highlight%20tumor%20cell%20state%20and%20immune%20dysfunction%20as%20key%20predictors%20and%20potential%20biomarkers%20of%20metastatic%20risk%20in%20ITM.%22%2C%22genre%22%3A%22%22%2C%22repository%22%3A%22bioRxiv%22%2C%22archiveID%22%3A%22%22%2C%22date%22%3A%222025-10-02%22%2C%22DOI%22%3A%2210.1101%5C%2F2025.10.01.679282%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22http%3A%5C%2F%5C%2Fbiorxiv.org%5C%2Flookup%5C%2Fdoi%5C%2F10.1101%5C%2F2025.10.01.679282%22%2C%22language%22%3A%22en%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-02-20T16%3A55%3A37Z%22%7D%7D%2C%7B%22key%22%3A%22FWBLYZH7%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Yapp%20et%20al.%22%2C%22parsedDate%22%3A%222025-09-29%22%2C%22numChildren%22%3A0%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EYapp%2C%20C.%2C%20Nirmal%2C%20A.%20J.%2C%20Zhou%2C%20F.%2C%20Wong%2C%20A.%20Y.%20H.%2C%20Tefft%2C%20J.%20B.%2C%20Lu%2C%20Y.%20D.%2C%20Shang%2C%20Z.%2C%20Maliga%2C%20Z.%2C%20Llopis%2C%20P.%20M.%2C%20Murphy%2C%20G.%20F.%2C%20Lian%2C%20C.%20G.%2C%20Danuser%2C%20G.%2C%20Santagata%2C%20S.%2C%20%26amp%3B%20Sorger%2C%20P.%20K.%20%282025%29.%20Highly%20multiplexed%203D%20profiling%20of%20cell%20states%20and%20immune%20niches%20in%20human%20tumors.%20%3Ci%3ENature%20Methods%3C%5C%2Fi%3E.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41592-025-02824-x%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41592-025-02824-x%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Highly%20multiplexed%203D%20profiling%20of%20cell%20states%20and%20immune%20niches%20in%20human%20tumors%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Clarence%22%2C%22lastName%22%3A%22Yapp%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ajit%20J.%22%2C%22lastName%22%3A%22Nirmal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Felix%22%2C%22lastName%22%3A%22Zhou%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alex%20Y.%20H.%22%2C%22lastName%22%3A%22Wong%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Juliann%20B.%22%2C%22lastName%22%3A%22Tefft%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yi%20Daniel%22%2C%22lastName%22%3A%22Lu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zhiguo%22%2C%22lastName%22%3A%22Shang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zoltan%22%2C%22lastName%22%3A%22Maliga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Paula%20Montero%22%2C%22lastName%22%3A%22Llopis%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22George%20F.%22%2C%22lastName%22%3A%22Murphy%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%20G.%22%2C%22lastName%22%3A%22Lian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gaudenz%22%2C%22lastName%22%3A%22Danuser%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sandro%22%2C%22lastName%22%3A%22Santagata%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%5D%2C%22abstractNote%22%3A%22Abstract%5Cn%20%20%20%20%20%20%20%20%20%20%20%20Diseases%20such%20as%20cancer%20involve%20alterations%20in%20cell%20proportions%2C%20states%20and%20interactions%2C%20as%20well%20as%20complex%20changes%20in%20tissue%20morphology%20and%20architecture.%20Histopathological%20diagnosis%20of%20disease%20and%20most%20multiplexed%20spatial%20profiling%20relies%20on%20inspecting%20thin%20%284%5Cu20135%5Cu2009%5Cu00b5m%29%20specimens.%20Here%20we%20describe%20a%20high-plex%20cyclic%20immunofluorescence%20method%20for%20three-dimensional%20tissue%20imaging%20and%20use%20it%20to%20show%20that%20few%2C%20if%20any%2C%20cells%20are%20intact%20in%20conventional%20thin%20tissue%20sections%2C%20reducing%20the%20accuracy%20of%20cell%20phenotyping%20and%20interaction%20analysis.%20However%2C%20three-dimensional%20cyclic%20immunofluorescence%20of%20sections%20eightfold%20to%20tenfold%20thicker%20enables%20accurate%20morphological%20assessment%20of%20diverse%20protein%20markers%20in%20intact%20tumor%2C%20immune%20and%20stromal%20cells.%20Moreover%2C%20the%20high%20resolution%20of%20this%20confocal%20approach%20generates%20images%20of%20cells%20in%20a%20preserved%20tissue%20environment%20at%20a%20level%20of%20detail%20previously%20limited%20to%20cell%20culture.%20Precise%20imaging%20of%20cell%20membranes%20also%20makes%20it%20possible%20to%20detect%20and%20map%20cell%5Cu2013cell%20contacts%20and%20juxtracrine%20signaling%20complexes%20in%20immune%20cell%20niches.%22%2C%22date%22%3A%222025-09-29%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1038%5C%2Fs41592-025-02824-x%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22https%3A%5C%2F%5C%2Fwww.nature.com%5C%2Farticles%5C%2Fs41592-025-02824-x%22%2C%22PMID%22%3A%22%22%2C%22PMCID%22%3A%22%22%2C%22ISSN%22%3A%221548-7091%2C%201548-7105%22%2C%22language%22%3A%22en%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-12-17T14%3A29%3A59Z%22%7D%7D%2C%7B%22key%22%3A%22RZGC87ZI%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Vallius%20et%20al.%22%2C%22parsedDate%22%3A%222025-06-24%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EVallius%2C%20T.%2C%20Shi%2C%20Y.%2C%20Novikov%2C%20E.%2C%20Pant%2C%20S.%20M.%2C%20Pelletier%2C%20R.%2C%20Chen%2C%20Y.-A.%2C%20Tefft%2C%20J.%20B.%2C%20Johnson%2C%20A.%20N.%2C%20Maliga%2C%20Z.%2C%20Wan%2C%20G.%2C%20Murphy%2C%20G.%2C%20Santagata%2C%20S.%2C%20Semenov%2C%20Y.%20R.%2C%20Liu%2C%20D.%2C%20Lian%2C%20C.%20G.%2C%20%26amp%3B%20Sorger%2C%20P.%20K.%20%282025%29.%20%3Ci%3ESpatial%20determinants%20of%20tumor%20cell%20dedifferentiation%20and%20plasticity%20in%20primary%20cutaneous%20melanoma%3C%5C%2Fi%3E.%20bioRxiv.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1101%5C%2F2025.06.21.660851%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1101%5C%2F2025.06.21.660851%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22preprint%22%2C%22title%22%3A%22Spatial%20determinants%20of%20tumor%20cell%20dedifferentiation%20and%20plasticity%20in%20primary%20cutaneous%20melanoma%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tuulia%22%2C%22lastName%22%3A%22Vallius%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yingxiao%22%2C%22lastName%22%3A%22Shi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Edward%22%2C%22lastName%22%3A%22Novikov%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shishir%20M%22%2C%22lastName%22%3A%22Pant%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Roxanne%22%2C%22lastName%22%3A%22Pelletier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yu-An%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Juliann%20B.%22%2C%22lastName%22%3A%22Tefft%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ajit%20Nirmal%22%2C%22lastName%22%3A%22Johnson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zoltan%22%2C%22lastName%22%3A%22Maliga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Guihong%22%2C%22lastName%22%3A%22Wan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22George%22%2C%22lastName%22%3A%22Murphy%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sandro%22%2C%22lastName%22%3A%22Santagata%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yevgeniy%20R%22%2C%22lastName%22%3A%22Semenov%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%20G%22%2C%22lastName%22%3A%22Lian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K%22%2C%22lastName%22%3A%22Sorger%22%7D%5D%2C%22abstractNote%22%3A%22ABSTRACT%5Cn%20%20%20%20%20%20%20%20%20%20Early%20detection%20of%20melanoma%20through%20skin%20surveillance%20is%20critical%20for%20preventing%20metastatic%20progression.%20Primary%20cutaneous%20melanomas%20at%20early%20stage%20offer%20a%20unique%20opportunity%20to%20uncover%20fundamental%20mechanisms%20of%20tumor%20initiation%2C%20progression%2C%20and%20immune%20surveillance%2C%20but%20detailed%20spatial%20profiling%20of%20early%20disease%20remains%20limited.%20Here%20we%20integrate%20high-plex%20cyclic%20immunofluorescence%20%28CyCIF%29%20imaging%2C%20spatial%20transcriptomics%2C%20and%20conventional%20histology%20to%20identify%20factors%20associated%20with%20de-differentiation%20and%20dermal%20invasion%20in%20early-stage%20melanomas.%20We%20demonstrate%20a%20high%20level%20of%20variability%20from%20one%20primary%20cancer%20to%20the%20next%2C%20from%20one%20100-300%20cell%20microregion%20to%20the%20next%20within%20a%20single%20cancer%2C%20and%20from%20one%20cell%20to%20the%20next%20within%20a%20microregion.%20Intra-tumoral%20heterogeneity%20is%20influenced%20by%20local%20features%20of%20the%20microenvironment%20including%20proximity%20to%20T%20and%20myeloid%20cells%20and%20to%20perivascular%20environments.%20Thus%2C%20tumor%20plasticity%20and%20spatial%20heterogeneity%20arise%20early%20in%20melanoma%20development%2C%20potentially%20allowing%20for%20competition%20among%20multiple%20tumor%20states%20during%20the%20emergence%20of%20invasive%20disease.%5Cn%20%20%20%20%20%20%20%20%20%20%5Cn%20%20%20%20%20%20%20%20%20%20%20%20STATEMENT%20OF%20SIGNIFICANCE%5Cn%20%20%20%20%20%20%20%20%20%20%20%20This%20study%20shows%20that%20tumor%20cell%20dedifferentiation%20and%20plasticity%20are%20locally%20patterned%20in%20primary%20human%20melanomas%20under%20the%20influence%20of%20microenvironment%20components%20such%20as%20myeloid%20cells%20and%20vasculature.%20As%20a%20result%2C%20neighborhoods%20in%20a%20single%20tumor%20can%20be%20as%20different%20from%20each%20other%20as%20in%20different%20tumors.%22%2C%22genre%22%3A%22%22%2C%22repository%22%3A%22bioRxiv%22%2C%22archiveID%22%3A%22%22%2C%22date%22%3A%222025-06-24%22%2C%22DOI%22%3A%2210.1101%5C%2F2025.06.21.660851%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22http%3A%5C%2F%5C%2Fbiorxiv.org%5C%2Flookup%5C%2Fdoi%5C%2F10.1101%5C%2F2025.06.21.660851%22%2C%22language%22%3A%22en%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-02-19T21%3A45%3A21Z%22%7D%7D%2C%7B%22key%22%3A%22H24MY7CY%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Fang%20et%20al.%22%2C%22parsedDate%22%3A%222025-05%22%2C%22numChildren%22%3A3%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EFang%2C%20R.%2C%20Vallius%2C%20T.%2C%20Zhang%2C%20A.%2C%20Van%20Cura%2C%20D.%2C%20Alicandri%2C%20F.%2C%20Fischer%2C%20G.%2C%20Draper%2C%20E.%2C%20Xu%2C%20S.%2C%20Pelletier%2C%20R.%2C%20Wang%2C%20J.%2C%20Mandinova%2C%20A.%2C%20Katsyv%2C%20I.%2C%20Sorger%2C%20P.%20K.%2C%20Murphy%2C%20G.%20F.%2C%20%26amp%3B%20Lian%2C%20C.%20G.%20%282025%29.%20PRAME%20Expression%20in%20Melanoma%20is%20Negatively%20Regulated%20by%20TET2-Mediated%20DNA%20Hydroxymethylation.%20%3Ci%3ELaboratory%20Investigation%3B%20a%20Journal%20of%20Technical%20Methods%20and%20Pathology%3C%5C%2Fi%3E%2C%20%3Ci%3E105%3C%5C%2Fi%3E%285%29%2C%20104123.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.labinv.2025.104123%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.labinv.2025.104123%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22PRAME%20Expression%20in%20Melanoma%20is%20Negatively%20Regulated%20by%20TET2-Mediated%20DNA%20Hydroxymethylation%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Rui%22%2C%22lastName%22%3A%22Fang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tuulia%22%2C%22lastName%22%3A%22Vallius%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Arianna%22%2C%22lastName%22%3A%22Zhang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Devon%22%2C%22lastName%22%3A%22Van%20Cura%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Francisco%22%2C%22lastName%22%3A%22Alicandri%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Grant%22%2C%22lastName%22%3A%22Fischer%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elizabeth%22%2C%22lastName%22%3A%22Draper%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shuyun%22%2C%22lastName%22%3A%22Xu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Roxanne%22%2C%22lastName%22%3A%22Pelletier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Justina%22%2C%22lastName%22%3A%22Wang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Anna%22%2C%22lastName%22%3A%22Mandinova%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Igor%22%2C%22lastName%22%3A%22Katsyv%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22George%20F.%22%2C%22lastName%22%3A%22Murphy%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%20G.%22%2C%22lastName%22%3A%22Lian%22%7D%5D%2C%22abstractNote%22%3A%22Preferentially%20expressed%20Antigen%20in%20Melanoma%20%28PRAME%29%20and%20Ten-Eleven%20Translocation%20%28TET%29%20dioxygenase-mediated%205-hydroxymethylcytosine%20%285hmC%29%20are%20emerging%20melanoma%20biomarkers.%20We%20observed%20an%20inverse%20correlation%20between%20PRAME%20expression%20and%205hmC%20levels%20in%20benign%20nevi%2C%20melanoma%20in%20situ%2C%20primary%20invasive%20melanoma%2C%20and%20metastatic%20melanomas%20via%20immunohistochemistry%20and%20multiplex%20immunofluorescence%3A%20nevi%20exhibited%20high%205hmC%20and%20low%20PRAME%2C%20whereas%20melanomas%20showed%20the%20opposite%20pattern.%20Single-cell%20multiplex%20imaging%20of%20melanoma%20precursors%20revealed%20that%20diminished%205hmC%20coincides%20with%20PRAME%20upregulation%20in%20premalignant%20cells.%20Analysis%20of%20The%20Cancer%20Genome%20Atlas%20and%20Genotype-Tissue%20Expression%20databases%20confirmed%20a%20negative%20relationship%20between%20TET2%20and%20PRAME%20messenger%20RNA%20expression%20in%20melanoma.%20Additionally%2C%205hmC%20levels%20were%20reduced%20at%20the%20PRAME%205%27%20promoter%20in%20melanoma%20compared%20with%20nevi%2C%20suggesting%20a%20role%20for%205hmC%20in%20PRAME%20transcription.%20Restoring%205hmC%20levels%20via%20TET2%20overexpression%20notably%20reduced%20PRAME%20expression%20in%20melanoma%20cell%20lines.%20These%20findings%20establish%20a%20function%20of%20TET2-mediated%20DNA%20hydroxymethylation%20in%20regulating%20PRAME%20expression%20and%20demonstrate%20epigenetic%20reprogramming%20as%20pivotal%20in%20melanoma%20tumorigenesis.%22%2C%22date%22%3A%222025-05%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1016%5C%2Fj.labinv.2025.104123%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2240024557%22%2C%22PMCID%22%3A%22%22%2C%22ISSN%22%3A%221530-0307%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-06-02T15%3A33%3A40Z%22%7D%7D%2C%7B%22key%22%3A%22QLUV5UXC%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Oka%20et%20al.%22%2C%22parsedDate%22%3A%222025-01%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EOka%2C%20T.%2C%20Hasegawa%2C%20T.%2C%20Lee%2C%20T.%2C%20Oliver-Garcia%2C%20V.%20S.%2C%20Mortaja%2C%20M.%2C%20Azin%2C%20M.%2C%20Horiba%2C%20S.%2C%20Smith%2C%20S.%20S.%2C%20Khattab%2C%20S.%2C%20Trerice%2C%20K.%20E.%2C%20Chen%2C%20S.%20T.%2C%20Semenov%2C%20Y.%20R.%2C%20%26amp%3B%20Demehri%2C%20S.%20%282025%29.%20Langerhans%20Cells%20Directly%20Interact%20with%20Resident%20T%20Cells%20in%20the%20Human%20Epidermis.%20%3Ci%3EJID%20Innovations%3A%20Skin%20Science%20from%20Molecules%20to%20Population%20Health%3C%5C%2Fi%3E%2C%20%3Ci%3E5%3C%5C%2Fi%3E%281%29%2C%20100324.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.xjidi.2024.100324%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.xjidi.2024.100324%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Langerhans%20Cells%20Directly%20Interact%20with%20Resident%20T%20Cells%20in%20the%20Human%20Epidermis%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tomonori%22%2C%22lastName%22%3A%22Oka%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tatsuya%22%2C%22lastName%22%3A%22Hasegawa%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Truelian%22%2C%22lastName%22%3A%22Lee%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Valeria%20S.%22%2C%22lastName%22%3A%22Oliver-Garcia%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mahsa%22%2C%22lastName%22%3A%22Mortaja%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Marjan%22%2C%22lastName%22%3A%22Azin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Satoshi%22%2C%22lastName%22%3A%22Horiba%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sabrina%20S.%22%2C%22lastName%22%3A%22Smith%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sara%22%2C%22lastName%22%3A%22Khattab%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kathryn%20E.%22%2C%22lastName%22%3A%22Trerice%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Steven%20T.%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yevgeniy%20R.%22%2C%22lastName%22%3A%22Semenov%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shadmehr%22%2C%22lastName%22%3A%22Demehri%22%7D%5D%2C%22abstractNote%22%3A%22Adult%20human%20skin%20contains%20nearly%20twice%20as%20many%20T%20cells%20as%20the%20peripheral%20blood%2C%20which%20include%20tissue-resident%20memory%20T%20cells.%20However%2C%20the%20precise%20mechanisms%20maintaining%20tissue-resident%20memory%20T%20cells%20in%20the%20healthy%20skin%20remain%20unclear.%20Using%20normal%20human%20skin%20samples%2C%20we%20find%20that%20Langerhans%20cells%20%28LCs%29%20contact%20T%20cells%20in%20the%20epidermis%20of%20the%20elderly.%20LCs%20with%20high%20HLA-II%2C%20CD86%2C%20and%20PD-L2%20expression%20directly%20contacted%20PD-1%2B%20tissue-resident%20memory%20T%20cells%20and%20CTLA-4%2B%20regulatory%20T%20cells%20in%20the%20epidermis%2C%20indicating%20an%20axis%20of%20peripheral%20tolerance%20in%20a%20steady%20state.%20Environmental%20insults%2C%20UVB%20radiation%2C%20and%20hapten%20downregulated%20HLA-II%20and%20CD86%20on%20LCs%20in%20the%20epidermis%2C%20suggesting%20that%20disruption%20of%20LC-T%20cell%20tolerogenic%20axis%20contributes%20to%20skin%20inflammation.%20Interestingly%2C%20immune%20checkpoint%20blockade%20therapy%20was%20associated%20with%20decreased%20epidermal%20LC-T%20cell%20contact%20in%20the%20normal%20skin%20of%20patients%20with%20cancer%20affected%20by%20cutaneous%20immune-related%20adverse%20events.%20Collectively%2C%20our%20findings%20indicate%20that%20LCs%20may%20contribute%20to%20T%20cell%20tolerance%20in%20the%20epidermis.%22%2C%22date%22%3A%222025-01%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1016%5C%2Fj.xjidi.2024.100324%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2239803386%22%2C%22PMCID%22%3A%22PMC11720605%22%2C%22ISSN%22%3A%222667-0267%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-02-11T14%3A04%3A22Z%22%7D%7D%2C%7B%22key%22%3A%22WX9E24YL%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Ma%20et%20al.%22%2C%22parsedDate%22%3A%222024-08-19%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EMa%2C%20Y.%2C%20Tagore%2C%20M.%2C%20Hunter%2C%20M.%20V.%2C%20Huang%2C%20T.-H.%2C%20Montal%2C%20E.%2C%20Weiss%2C%20J.%20M.%2C%20Shi%2C%20Y.%2C%20Vallius%2C%20T.%2C%20Sorger%2C%20P.%20K.%2C%20%26amp%3B%20White%2C%20R.%20M.%20%282024%29.%20%3Ci%3ERestraint%20of%20melanoma%20progression%20by%20cells%20in%20the%20local%20skin%20environment%3C%5C%2Fi%3E.%20Cancer%20Biology.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1101%5C%2F2024.08.15.608067%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1101%5C%2F2024.08.15.608067%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22preprint%22%2C%22title%22%3A%22Restraint%20of%20melanoma%20progression%20by%20cells%20in%20the%20local%20skin%20environment%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yilun%22%2C%22lastName%22%3A%22Ma%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mohita%22%2C%22lastName%22%3A%22Tagore%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Miranda%20V.%22%2C%22lastName%22%3A%22Hunter%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ting-Hsiang%22%2C%22lastName%22%3A%22Huang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Emily%22%2C%22lastName%22%3A%22Montal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Joshua%20M.%22%2C%22lastName%22%3A%22Weiss%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yingxiao%22%2C%22lastName%22%3A%22Shi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tuulia%22%2C%22lastName%22%3A%22Vallius%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Richard%20M.%22%2C%22lastName%22%3A%22White%22%7D%5D%2C%22abstractNote%22%3A%22Abstract%5Cn%20%20%20%20%20%20%20%20%20%20Keratinocytes%2C%20the%20dominant%20cell%20type%20in%20the%20melanoma%20microenvironment%20during%20tumor%20initiation%2C%20exhibit%20diverse%20effects%20on%20melanoma%20progression.%20Using%20a%20zebrafish%20model%20of%20melanoma%20and%20human%20cell%20co-cultures%2C%20we%20observed%20that%20keratinocytes%20undergo%20an%20EMT-like%20transformation%20in%20the%20presence%20of%20melanoma%2C%20reminiscent%20of%20their%20behavior%20during%20wound%20healing.%20Surprisingly%2C%20overexpression%20of%20the%20EMT%20transcription%20factor%20Twist%20in%20keratinocytes%20led%20to%20improved%20overall%20survival%20in%20zebrafish%20melanoma%20models%2C%20despite%20no%20change%20in%20tumor%20initiation%20rates.%20This%20survival%20benefit%20was%20attributed%20to%20reduced%20melanoma%20invasion%2C%20as%20confirmed%20by%20human%20cell%20co-culture%20assays.%20Single-cell%20RNA-sequencing%20revealed%20a%20unique%20melanoma%20cell%20cluster%20in%20the%20Twist-overexpressing%20condition%2C%20exhibiting%20a%20more%20differentiated%2C%20less%20invasive%20phenotype.%20Further%20analysis%20nominated%20homotypic%20jam3b-jam3b%20and%20pgrn-sort1a%20interactions%20between%20Twist-overexpressing%20keratinocytes%20and%20melanoma%20cells%20as%20potential%20mediators%20of%20the%20invasive%20restraint.%20Our%20findings%20suggest%20that%20EMT%20in%20the%20tumor%20microenvironment%20may%20paradoxically%20limit%20melanoma%20invasion%20through%20altered%20cell-cell%20interactions.%22%2C%22genre%22%3A%22%22%2C%22repository%22%3A%22Cancer%20Biology%22%2C%22archiveID%22%3A%22%22%2C%22date%22%3A%222024-08-19%22%2C%22DOI%22%3A%2210.1101%5C%2F2024.08.15.608067%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22http%3A%5C%2F%5C%2Fbiorxiv.org%5C%2Flookup%5C%2Fdoi%5C%2F10.1101%5C%2F2024.08.15.608067%22%2C%22language%22%3A%22en%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222026-03-23T17%3A19%3A08Z%22%7D%7D%2C%7B%22key%22%3A%22MIHTMUEJ%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Rogava%20et%20al.%22%2C%22parsedDate%22%3A%222024-03%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ERogava%2C%20M.%2C%20Aprati%2C%20T.%20J.%2C%20Chi%2C%20W.-Y.%2C%20Melms%2C%20J.%20C.%2C%20Hug%2C%20C.%2C%20Davis%2C%20S.%20H.%2C%20Earlie%2C%20E.%20M.%2C%20Chung%2C%20C.%2C%20Deshmukh%2C%20S.%20K.%2C%20Wu%2C%20S.%2C%20Sledge%2C%20G.%2C%20Tang%2C%20S.%2C%20Ho%2C%20P.%2C%20Amin%2C%20A.%20D.%2C%20Caprio%2C%20L.%2C%20Gurjao%2C%20C.%2C%20Tagore%2C%20S.%2C%20Ngo%2C%20B.%2C%20Lee%2C%20M.%20J.%2C%20%26%23x2026%3B%20Izar%2C%20B.%20%282024%29.%20Loss%20of%20Pip4k2c%20confers%20liver-metastatic%20organotropism%20through%20insulin-dependent%20PI3K-AKT%20pathway%20activation.%20%3Ci%3ENature%20Cancer%3C%5C%2Fi%3E%2C%20%3Ci%3E5%3C%5C%2Fi%3E%283%29%2C%20433%26%23x2013%3B447.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs43018-023-00704-x%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs43018-023-00704-x%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Loss%20of%20Pip4k2c%20confers%20liver-metastatic%20organotropism%20through%20insulin-dependent%20PI3K-AKT%20pathway%20activation%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Meri%22%2C%22lastName%22%3A%22Rogava%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tyler%20J.%22%2C%22lastName%22%3A%22Aprati%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Wei-Yu%22%2C%22lastName%22%3A%22Chi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Johannes%20C.%22%2C%22lastName%22%3A%22Melms%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Clemens%22%2C%22lastName%22%3A%22Hug%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Stephanie%20H.%22%2C%22lastName%22%3A%22Davis%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ethan%20M.%22%2C%22lastName%22%3A%22Earlie%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Charlie%22%2C%22lastName%22%3A%22Chung%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sachin%20K.%22%2C%22lastName%22%3A%22Deshmukh%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sharon%22%2C%22lastName%22%3A%22Wu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22George%22%2C%22lastName%22%3A%22Sledge%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Stephen%22%2C%22lastName%22%3A%22Tang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Patricia%22%2C%22lastName%22%3A%22Ho%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Amit%20Dipak%22%2C%22lastName%22%3A%22Amin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lindsay%22%2C%22lastName%22%3A%22Caprio%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Carino%22%2C%22lastName%22%3A%22Gurjao%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Somnath%22%2C%22lastName%22%3A%22Tagore%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bryan%22%2C%22lastName%22%3A%22Ngo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Michael%20J.%22%2C%22lastName%22%3A%22Lee%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Giorgia%22%2C%22lastName%22%3A%22Zanetti%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yiping%22%2C%22lastName%22%3A%22Wang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sean%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22William%22%2C%22lastName%22%3A%22Ge%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Luiza%20Martins%20Nascentes%22%2C%22lastName%22%3A%22Melo%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gabriele%22%2C%22lastName%22%3A%22Allies%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jonas%22%2C%22lastName%22%3A%22R%5Cu00f6sler%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Goeffrey%20T.%22%2C%22lastName%22%3A%22Gibney%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Oliver%20J.%22%2C%22lastName%22%3A%22Schmitz%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Megan%22%2C%22lastName%22%3A%22Sykes%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22R%5Cu00e9mi%20J.%22%2C%22lastName%22%3A%22Creusot%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Thomas%22%2C%22lastName%22%3A%22T%5Cu00fcting%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Dirk%22%2C%22lastName%22%3A%22Schadendorf%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Martin%22%2C%22lastName%22%3A%22R%5Cu00f6cken%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Thomas%20K.%22%2C%22lastName%22%3A%22Eigentler%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Andrei%22%2C%22lastName%22%3A%22Molotkov%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Akiva%22%2C%22lastName%22%3A%22Mintz%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Samuel%20F.%22%2C%22lastName%22%3A%22Bakhoum%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Semir%22%2C%22lastName%22%3A%22Beyaz%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lewis%20C.%22%2C%22lastName%22%3A%22Cantley%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sven%20W.%22%2C%22lastName%22%3A%22Meckelmann%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alpaslan%22%2C%22lastName%22%3A%22Tasdogan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ashley%20M.%22%2C%22lastName%22%3A%22Laughney%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benjamin%22%2C%22lastName%22%3A%22Izar%22%7D%5D%2C%22abstractNote%22%3A%22Liver%20metastasis%20%28LM%29%20confers%20poor%20survival%20and%20therapy%20resistance%20across%20cancer%20types%2C%20but%20the%20mechanisms%20of%20liver-metastatic%20organotropism%20remain%20unknown.%20Here%2C%20through%20in%20vivo%20CRISPR-Cas9%20screens%2C%20we%20found%20that%20Pip4k2c%20loss%20conferred%20LM%20but%20had%20no%20impact%20on%20lung%20metastasis%20or%20primary%20tumor%20growth.%20Pip4k2c-deficient%20cells%20were%20hypersensitized%20to%20insulin-mediated%20PI3K%5C%2FAKT%20signaling%20and%20exploited%20the%20insulin-rich%20liver%20milieu%20for%20organ-specific%20metastasis.%20We%20observed%20concordant%20changes%20in%20PIP4K2C%20expression%20and%20distinct%20metabolic%20changes%20in%203%2C511%20patient%20melanomas%2C%20including%20primary%20tumors%2C%20LMs%20and%20lung%20metastases.%20We%20found%20that%20systemic%20PI3K%20inhibition%20exacerbated%20LM%20burden%20in%20mice%20injected%20with%20Pip4k2c-deficient%20cancer%20cells%20through%20host-mediated%20increase%20in%20hepatic%20insulin%20levels%3B%20however%2C%20this%20circuit%20could%20be%20broken%20by%20concurrent%20administration%20of%20an%20SGLT2%20inhibitor%20or%20feeding%20of%20a%20ketogenic%20diet.%20Thus%2C%20this%20work%20demonstrates%20a%20rare%20example%20of%20metastatic%20organotropism%20through%20co-optation%20of%20physiological%20metabolic%20cues%20and%20proposes%20therapeutic%20avenues%20to%20counteract%20these%20mechanisms.%22%2C%22date%22%3A%222024-03%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1038%5C%2Fs43018-023-00704-x%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2238286827%22%2C%22PMCID%22%3A%22PMC11175596%22%2C%22ISSN%22%3A%222662-1347%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-12-18T00%3A09%3A46Z%22%7D%7D%2C%7B%22key%22%3A%22B9LJZ4QE%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Zhang%20et%20al.%22%2C%22parsedDate%22%3A%222024-01-20%22%2C%22numChildren%22%3A2%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EZhang%2C%20X.%2C%20Pant%2C%20S.%20M.%2C%20Ritch%2C%20C.%20C.%2C%20Tang%2C%20H.-Y.%2C%20Shao%2C%20H.%2C%20Dweep%2C%20H.%2C%20Gong%2C%20Y.-Y.%2C%20Brooks%2C%20R.%2C%20Brafford%2C%20P.%2C%20Wolpaw%2C%20A.%20J.%2C%20Lee%2C%20Y.%2C%20Weeraratna%2C%20A.%2C%20Sehgal%2C%20A.%2C%20Herlyn%2C%20M.%2C%20Kossenkov%2C%20A.%2C%20Speicher%2C%20D.%2C%20Sorger%2C%20P.%20K.%2C%20Santagata%2C%20S.%2C%20%26amp%3B%20Dang%2C%20C.%20V.%20%282024%29.%20Cell%20state%20dependent%20effects%20of%20Bmal1%20on%20melanoma%20immunity%20and%20tumorigenicity.%20%3Ci%3ENature%20Communications%3C%5C%2Fi%3E%2C%20%3Ci%3E15%3C%5C%2Fi%3E%281%29%2C%20633.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41467-024-44778-2%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41467-024-44778-2%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Cell%20state%20dependent%20effects%20of%20Bmal1%20on%20melanoma%20immunity%20and%20tumorigenicity%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Xue%22%2C%22lastName%22%3A%22Zhang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shishir%20M.%22%2C%22lastName%22%3A%22Pant%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Cecily%20C.%22%2C%22lastName%22%3A%22Ritch%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hsin-Yao%22%2C%22lastName%22%3A%22Tang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hongguang%22%2C%22lastName%22%3A%22Shao%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Harsh%22%2C%22lastName%22%3A%22Dweep%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yao-Yu%22%2C%22lastName%22%3A%22Gong%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Rebekah%22%2C%22lastName%22%3A%22Brooks%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Patricia%22%2C%22lastName%22%3A%22Brafford%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Adam%20J.%22%2C%22lastName%22%3A%22Wolpaw%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yool%22%2C%22lastName%22%3A%22Lee%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ashani%22%2C%22lastName%22%3A%22Weeraratna%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Amita%22%2C%22lastName%22%3A%22Sehgal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Meenhard%22%2C%22lastName%22%3A%22Herlyn%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Andrew%22%2C%22lastName%22%3A%22Kossenkov%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Speicher%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sandro%22%2C%22lastName%22%3A%22Santagata%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Chi%20V.%22%2C%22lastName%22%3A%22Dang%22%7D%5D%2C%22abstractNote%22%3A%22The%20circadian%20clock%20regulator%20Bmal1%20modulates%20tumorigenesis%2C%20but%20its%20reported%20effects%20are%20inconsistent.%20Here%2C%20we%20show%20that%20Bmal1%20has%20a%20context-dependent%20role%20in%20mouse%20melanoma%20tumor%20growth.%20Loss%20of%20Bmal1%20in%20YUMM2.1%20or%20B16-F10%20melanoma%20cells%20eliminates%20clock%20function%20and%20diminishes%20hypoxic%20gene%20expression%20and%20tumorigenesis%2C%20which%20could%20be%20rescued%20by%20ectopic%20expression%20of%20HIF1%5Cu03b1%20in%20YUMM2.1%20cells.%20By%20contrast%2C%20over-expressed%20wild-type%20or%20a%20transcriptionally%20inactive%20mutant%20Bmal1%20non-canonically%20sequester%20myosin%20heavy%20chain%209%20%28Myh9%29%20to%20increase%20MRTF-SRF%20activity%20and%20AP-1%20transcriptional%20signature%2C%20and%20shift%20YUMM2.1%20cells%20from%20a%20Sox10high%20to%20a%20Sox9high%20immune%20resistant%2C%20mesenchymal%20cell%20state%20that%20is%20found%20in%20human%20melanomas.%20Our%20work%20describes%20a%20link%20between%20Bmal1%2C%20Myh9%2C%20mouse%20melanoma%20cell%20plasticity%2C%20and%20tumor%20immunity.%20This%20connection%20may%20underlie%20cancer%20therapeutic%20resistance%20and%20underpin%20the%20link%20between%20the%20circadian%20clock%2C%20MRTF-SRF%20and%20the%20cytoskeleton.%22%2C%22date%22%3A%222024-01-20%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1038%5C%2Fs41467-024-44778-2%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2238245503%22%2C%22PMCID%22%3A%22PMC10799901%22%2C%22ISSN%22%3A%222041-1723%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-12-17T16%3A42%3A54Z%22%7D%7D%2C%7B%22key%22%3A%225CPN6IGT%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Wan%20et%20al.%22%2C%22parsedDate%22%3A%222023-10-03%22%2C%22numChildren%22%3A1%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EWan%2C%20G.%2C%20Leung%2C%20B.%20W.%2C%20DeSimone%2C%20M.%20S.%2C%20Nguyen%2C%20N.%2C%20Rajeh%2C%20A.%2C%20Collier%2C%20M.%20R.%2C%20Rashdan%2C%20H.%2C%20Roster%2C%20K.%2C%20Zhou%2C%20X.%2C%20Moseley%2C%20C.%20B.%2C%20Nirmal%2C%20A.%20J.%2C%20Pelletier%2C%20R.%20J.%2C%20Maliga%2C%20Z.%2C%20Marko-Varga%2C%20G.%2C%20N%26%23xE9%3Bmeth%2C%20I.%20B.%2C%20Tsao%2C%20H.%2C%20Asgari%2C%20M.%20M.%2C%20Gusev%2C%20A.%2C%20Stagner%2C%20A.%20M.%2C%20%26%23x2026%3B%20Semenov%2C%20Y.%20R.%20%282023%29.%20Development%20and%20validation%20of%20time-to-event%20models%20to%20predict%20metastatic%20recurrence%20of%20localized%20cutaneous%20melanoma.%20%3Ci%3EJournal%20of%20the%20American%20Academy%20of%20Dermatology%3C%5C%2Fi%3E%2C%20S0190-9622%2823%2902881-5.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.jaad.2023.08.105%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.jaad.2023.08.105%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Development%20and%20validation%20of%20time-to-event%20models%20to%20predict%20metastatic%20recurrence%20of%20localized%20cutaneous%20melanoma%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Guihong%22%2C%22lastName%22%3A%22Wan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bonnie%20W.%22%2C%22lastName%22%3A%22Leung%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mia%20S.%22%2C%22lastName%22%3A%22DeSimone%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nga%22%2C%22lastName%22%3A%22Nguyen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ahmad%22%2C%22lastName%22%3A%22Rajeh%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Michael%20R.%22%2C%22lastName%22%3A%22Collier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hannah%22%2C%22lastName%22%3A%22Rashdan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Katie%22%2C%22lastName%22%3A%22Roster%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Xu%22%2C%22lastName%22%3A%22Zhou%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Cameron%20B.%22%2C%22lastName%22%3A%22Moseley%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ajit%20J.%22%2C%22lastName%22%3A%22Nirmal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Roxanne%20J.%22%2C%22lastName%22%3A%22Pelletier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zoltan%22%2C%22lastName%22%3A%22Maliga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gyorgy%22%2C%22lastName%22%3A%22Marko-Varga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Istv%5Cu00e1n%20Bal%5Cu00e1zs%22%2C%22lastName%22%3A%22N%5Cu00e9meth%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Hensin%22%2C%22lastName%22%3A%22Tsao%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Maryam%20M.%22%2C%22lastName%22%3A%22Asgari%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alexander%22%2C%22lastName%22%3A%22Gusev%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Anna%20M.%22%2C%22lastName%22%3A%22Stagner%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%20G.%22%2C%22lastName%22%3A%22Lian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Marc%20S.%22%2C%22lastName%22%3A%22Hurlbert%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Feng%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kun-Hsing%22%2C%22lastName%22%3A%22Yu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yevgeniy%20R.%22%2C%22lastName%22%3A%22Semenov%22%7D%5D%2C%22abstractNote%22%3A%22BACKGROUND%3A%20The%20recent%20expansion%20of%20immunotherapy%20for%20stage%20IIB%5C%2FIIC%20melanoma%20highlights%20a%20growing%20clinical%20need%20to%20identify%20patients%20at%20high%20risk%20of%20metastatic%20recurrence%20and%2C%20therefore%2C%20most%20likely%20to%20benefit%20from%20this%20therapeutic%20modality.%5CnOBJECTIVE%3A%20To%20develop%20time-to-event%20risk%20prediction%20models%20for%20melanoma%20metastatic%20recurrence.%5CnMETHODS%3A%20Patients%20diagnosed%20with%20stage%20I%5C%2FII%20primary%20cutaneous%20melanoma%20between%202000%20and%202020%20at%20Mass%20General%20Brigham%20and%20Dana-Farber%20Cancer%20Institute%20were%20included.%20Melanoma%20recurrence%20date%20and%20type%20were%20determined%20by%20chart%20review.%20Thirty%20clinicopathologic%20factors%20were%20extracted%20from%20electronic%20health%20records.%20Three%20types%20of%20time-to-event%20machine-learning%20models%20were%20evaluated%20internally%20and%20externally%20in%20the%20distant%20versus%20locoregional%5C%2Fnon-recurrence%20prediction.%5CnRESULTS%3A%20This%20study%20included%20954%20melanomas%20%28155%20distant%2C%20163%20locoregional%2C%20and%20636%201%3A2%20matched%20non-recurrences%29.%20Distant%20recurrences%20were%20associated%20with%20worse%20survival%20compared%20to%20locoregional%5C%2Fnon-recurrences%20%28HR%3A%206.21%2C%20p%3C0.001%29%20and%20to%20locoregional%20recurrences%20only%20%28HR%3A%205.79%2C%20p%3C0.001%29.%20The%20Gradient%20Boosting%20Survival%20model%20achieved%20the%20best%20performance%20%28concordance%20index%3A%200.816%3B%20time-dependent%20AUC%3A%200.842%3B%20Brier%20score%3A%200.103%29%20in%20the%20external%20validation.%5CnLIMITATIONS%3A%20Retrospective%20nature%20and%20cohort%20from%20one%20geography.%5CnCONCLUSIONS%3A%20These%20results%20suggest%20that%20time-to-event%20machine-learning%20models%20can%20reliably%20predict%20the%20metastatic%20recurrence%20from%20localized%20melanoma%20and%20help%20identify%20high-risk%20patients%20who%20are%20most%20likely%20to%20benefit%20from%20immunotherapy.%22%2C%22date%22%3A%222023-10-03%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1016%5C%2Fj.jaad.2023.08.105%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2237797836%22%2C%22PMCID%22%3A%22%22%2C%22ISSN%22%3A%221097-6787%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-12-17T16%3A45%3A19Z%22%7D%7D%2C%7B%22key%22%3A%22NU4N67K7%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Fr%5Cu00f6hlich%20et%20al.%22%2C%22parsedDate%22%3A%222023-02-10%22%2C%22numChildren%22%3A2%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EFr%26%23xF6%3Bhlich%2C%20F.%2C%20Gerosa%2C%20L.%2C%20Muhlich%2C%20J.%2C%20%26amp%3B%20Sorger%2C%20P.%20K.%20%282023%29.%20Mechanistic%20model%20of%20MAPK%20signaling%20reveals%20how%20allostery%20and%20rewiring%20contribute%20to%20drug%20resistance.%20%3Ci%3EMolecular%20Systems%20Biology%3C%5C%2Fi%3E%2C%20%3Ci%3E19%3C%5C%2Fi%3E%282%29%2C%20e10988.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.15252%5C%2Fmsb.202210988%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.15252%5C%2Fmsb.202210988%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Mechanistic%20model%20of%20MAPK%20signaling%20reveals%20how%20allostery%20and%20rewiring%20contribute%20to%20drug%20resistance%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Fabian%22%2C%22lastName%22%3A%22Fr%5Cu00f6hlich%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Luca%22%2C%22lastName%22%3A%22Gerosa%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jeremy%22%2C%22lastName%22%3A%22Muhlich%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%5D%2C%22abstractNote%22%3A%22BRAF%20is%20prototypical%20of%20oncogenes%20that%20can%20be%20targeted%20therapeutically%20and%20the%20treatment%20of%20BRAFV600E%20melanomas%20with%20RAF%20and%20MEK%20inhibitors%20results%20in%20rapid%20tumor%20regression.%20However%2C%20drug-induced%20rewiring%20generates%20a%20drug%20adapted%20state%20thought%20to%20be%20involved%20in%20acquired%20resistance%20and%20disease%20recurrence.%20In%20this%20article%2C%20we%20study%20mechanisms%20of%20adaptive%20rewiring%20in%20BRAFV600E%20melanoma%20cells%20using%20an%20energy-based%20implementation%20of%20ordinary%20differential%20equation%5Cu00a0%28ODE%29%20modeling%20in%20combination%20with%20proteomic%2C%20transcriptomic%20and%20imaging%20data.%20We%20develop%20a%20method%20for%20causal%20tracing%20of%20ODE%20models%20and%20identify%20two%20parallel%20MAPK%20reaction%20channels%20that%20are%20differentially%20sensitive%20to%20RAF%20and%20MEK%20inhibitors%20due%20to%20differences%20in%20protein%20oligomerization%20and%20drug%20binding.%20We%20describe%20how%20these%20channels%2C%20and%20timescale%20separation%20between%20immediate-early%20signaling%20and%20transcriptional%20feedback%2C%20create%20a%20state%20in%20which%20the%20RAS-regulated%20MAPK%20channel%20can%20be%20activated%20by%20growth%20factors%20under%20conditions%20in%20which%20the%20BRAFV600E%20-driven%20channel%20is%20fully%20inhibited.%20Further%20development%20of%20the%20approaches%20in%20this%20article%20is%20expected%20to%20yield%20a%20unified%20model%20of%20adaptive%20drug%20resistance%20in%20melanoma.%22%2C%22date%22%3A%222023-02-10%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.15252%5C%2Fmsb.202210988%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2236700386%22%2C%22PMCID%22%3A%22PMC9912026%22%2C%22ISSN%22%3A%221744-4292%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222024-10-31T19%3A19%3A19Z%22%7D%7D%2C%7B%22key%22%3A%22RDKDE8NJ%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Nirmal%20et%20al.%22%2C%22parsedDate%22%3A%222022-06-02%22%2C%22numChildren%22%3A4%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ENirmal%2C%20A.%20J.%2C%20Maliga%2C%20Z.%2C%20Vallius%2C%20T.%2C%20Quattrochi%2C%20B.%2C%20Chen%2C%20A.%20A.%2C%20Jacobson%2C%20C.%20A.%2C%20Pelletier%2C%20R.%20J.%2C%20Yapp%2C%20C.%2C%20Arias-Camison%2C%20R.%2C%20Chen%2C%20Y.-A.%2C%20Lian%2C%20C.%20G.%2C%20Murphy%2C%20G.%20F.%2C%20Santagata%2C%20S.%2C%20%26amp%3B%20Sorger%2C%20P.%20K.%20%282022%29.%20The%20spatial%20landscape%20of%20progression%20and%20immunoediting%20in%20primary%20melanoma%20at%20single-cell%20resolution.%20%3Ci%3ECancer%20Discovery%3C%5C%2Fi%3E%2C%20%3Ci%3E12%3C%5C%2Fi%3E%286%29%2C%201518%26%23x2013%3B1541.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1158%5C%2F2159-8290.CD-21-1357%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1158%5C%2F2159-8290.CD-21-1357%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22The%20spatial%20landscape%20of%20progression%20and%20immunoediting%20in%20primary%20melanoma%20at%20single-cell%20resolution%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ajit%20J.%22%2C%22lastName%22%3A%22Nirmal%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zoltan%22%2C%22lastName%22%3A%22Maliga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tuulia%22%2C%22lastName%22%3A%22Vallius%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Brian%22%2C%22lastName%22%3A%22Quattrochi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alyce%20A.%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Connor%20A.%22%2C%22lastName%22%3A%22Jacobson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Roxanne%20J.%22%2C%22lastName%22%3A%22Pelletier%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Clarence%22%2C%22lastName%22%3A%22Yapp%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Raquel%22%2C%22lastName%22%3A%22Arias-Camison%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yu-An%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%20G.%22%2C%22lastName%22%3A%22Lian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22George%20F.%22%2C%22lastName%22%3A%22Murphy%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sandro%22%2C%22lastName%22%3A%22Santagata%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%5D%2C%22abstractNote%22%3A%22Cutaneous%20melanoma%20is%20a%20highly%20immunogenic%20malignancy%20that%20is%20surgically%20curable%20at%20early%20stages%20but%20life-threatening%20when%20metastatic.%20Here%20we%20integrate%20high-plex%20imaging%2C%203D%20high-resolution%20microscopy%2C%20and%20spatially%20resolved%20microregion%20transcriptomics%20to%20study%20immune%20evasion%20and%20immunoediting%20in%20primary%20melanoma.%20We%20find%20that%20recurrent%20cellular%20neighborhoods%20involving%20tumor%2C%20immune%2C%20and%20stromal%20cells%20change%20significantly%20along%20a%20progression%20axis%20involving%20precursor%20states%2C%20melanoma%20in%20situ%2C%20and%20invasive%20tumor.%20Hallmarks%20of%20immunosuppression%20are%20already%20detectable%20in%20precursor%20regions.%20When%20tumors%20become%20locally%20invasive%2C%20a%20consolidated%20and%20spatially%20restricted%20suppressive%20environment%20forms%20along%20the%20tumor-stromal%20boundary.%20This%20environment%20is%20established%20by%20cytokine%20gradients%20that%20promote%20expression%20of%20MHC-II%20and%20IDO1%2C%20and%20by%20PD1-PDL1-mediated%20cell%20contacts%20involving%20macrophages%2C%20dendritic%20cells%2C%20and%20T%20cells.%20A%20few%20millimeters%20away%2C%20cytotoxic%20T%20cells%20synapse%20with%20melanoma%20cells%20in%20fields%20of%20tumor%20regression.%20Thus%2C%20invasion%20and%20immunoediting%20can%20coexist%20within%20a%20few%20millimeters%20of%20each%20other%20in%20a%20single%20specimen.%5CnSIGNIFICANCE%3A%20The%20reorganization%20of%20the%20tumor%20ecosystem%20in%20primary%20melanoma%20is%20an%20excellent%20setting%20in%20which%20to%20study%20immunoediting%20and%20immune%20evasion.%20Guided%20by%20classic%20histopathology%2C%20spatial%20profiling%20of%20proteins%20and%20mRNA%20reveals%20recurrent%20morphologic%20and%20molecular%20features%20of%20tumor%20evolution%20that%20involve%20localized%20paracrine%20cytokine%20signaling%20and%20direct%20cell-cell%20contact.%20This%20article%20is%20highlighted%20in%20the%20In%20This%20Issue%20feature%2C%20p.%201397.%22%2C%22date%22%3A%222022-06-02%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1158%5C%2F2159-8290.CD-21-1357%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2235404441%22%2C%22PMCID%22%3A%22PMC9167783%22%2C%22ISSN%22%3A%222159-8290%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-12-17T14%3A32%3A18Z%22%7D%7D%2C%7B%22key%22%3A%22I83Z39LS%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Hodis%20et%20al.%22%2C%22parsedDate%22%3A%222022-04-29%22%2C%22numChildren%22%3A2%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EHodis%2C%20E.%2C%20Torlai%20Triglia%2C%20E.%2C%20Kwon%2C%20J.%20Y.%20H.%2C%20Biancalani%2C%20T.%2C%20Zakka%2C%20L.%20R.%2C%20Parkar%2C%20S.%2C%20H%26%23xFC%3Btter%2C%20J.-C.%2C%20Buffoni%2C%20L.%2C%20Delorey%2C%20T.%20M.%2C%20Phillips%2C%20D.%2C%20Dionne%2C%20D.%2C%20Nguyen%2C%20L.%20T.%2C%20Schapiro%2C%20D.%2C%20Maliga%2C%20Z.%2C%20Jacobson%2C%20C.%20A.%2C%20Hendel%2C%20A.%2C%20Rozenblatt-Rosen%2C%20O.%2C%20Mihm%2C%20M.%20C.%2C%20Garraway%2C%20L.%20A.%2C%20%26amp%3B%20Regev%2C%20A.%20%282022%29.%20Stepwise-edited%2C%20human%20melanoma%20models%20reveal%20mutations%26%23x2019%3B%20effect%20on%20tumor%20and%20microenvironment.%20%3Ci%3EScience%20%28New%20York%2C%20N.Y.%29%3C%5C%2Fi%3E%2C%20%3Ci%3E376%3C%5C%2Fi%3E%286592%29%2C%20eabi8175.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1126%5C%2Fscience.abi8175%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1126%5C%2Fscience.abi8175%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Stepwise-edited%2C%20human%20melanoma%20models%20reveal%20mutations%27%20effect%20on%20tumor%20and%20microenvironment%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Eran%22%2C%22lastName%22%3A%22Hodis%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elena%22%2C%22lastName%22%3A%22Torlai%20Triglia%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22John%20Y.%20H.%22%2C%22lastName%22%3A%22Kwon%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tommaso%22%2C%22lastName%22%3A%22Biancalani%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Labib%20R.%22%2C%22lastName%22%3A%22Zakka%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Saurabh%22%2C%22lastName%22%3A%22Parkar%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jan-Christian%22%2C%22lastName%22%3A%22H%5Cu00fctter%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lorenzo%22%2C%22lastName%22%3A%22Buffoni%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Toni%20M.%22%2C%22lastName%22%3A%22Delorey%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Devan%22%2C%22lastName%22%3A%22Phillips%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Danielle%22%2C%22lastName%22%3A%22Dionne%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lan%20T.%22%2C%22lastName%22%3A%22Nguyen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Denis%22%2C%22lastName%22%3A%22Schapiro%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Zoltan%22%2C%22lastName%22%3A%22Maliga%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Connor%20A.%22%2C%22lastName%22%3A%22Jacobson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ayal%22%2C%22lastName%22%3A%22Hendel%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Orit%22%2C%22lastName%22%3A%22Rozenblatt-Rosen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Martin%20C.%22%2C%22lastName%22%3A%22Mihm%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Levi%20A.%22%2C%22lastName%22%3A%22Garraway%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Aviv%22%2C%22lastName%22%3A%22Regev%22%7D%5D%2C%22abstractNote%22%3A%22Establishing%20causal%20relationships%20between%20genetic%20alterations%20of%20human%20cancers%20and%20specific%20phenotypes%20of%20malignancy%20remains%20a%20challenge.%20We%20sequentially%20introduced%20mutations%20into%20healthy%20human%20melanocytes%20in%20up%20to%20five%20genes%20spanning%20six%20commonly%20disrupted%20melanoma%20pathways%2C%20forming%20nine%20genetically%20distinct%20cellular%20models%20of%20melanoma.%20We%20connected%20mutant%20melanocyte%20genotypes%20to%20malignant%20cell%20expression%20programs%20in%20vitro%20and%20in%20vivo%2C%20replicative%20immortality%2C%20malignancy%2C%20rapid%20tumor%20growth%2C%20pigmentation%2C%20metastasis%2C%20and%20histopathology.%20Mutations%20in%20malignant%20cells%20also%20affected%20tumor%20microenvironment%20composition%20and%20cell%20states.%20Our%20melanoma%20models%20shared%20genotype-associated%20expression%20programs%20with%20patient%20melanomas%2C%20and%20a%20deep%20learning%20model%20showed%20that%20these%20models%20partially%20recapitulated%20genotype-associated%20histopathological%20features%20as%20well.%20Thus%2C%20a%20progressive%20series%20of%20genome-edited%20human%20cancer%20models%20can%20causally%20connect%20genotypes%20carrying%20multiple%20mutations%20to%20phenotype.%22%2C%22date%22%3A%222022-04-29%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1126%5C%2Fscience.abi8175%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2235482859%22%2C%22PMCID%22%3A%22PMC9427199%22%2C%22ISSN%22%3A%221095-9203%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-01-29T10%3A34%3A58Z%22%7D%7D%2C%7B%22key%22%3A%22ZVK65ANP%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Liu%20et%20al.%22%2C%22parsedDate%22%3A%222021-06%22%2C%22numChildren%22%3A5%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3ELiu%2C%20D.%2C%20Lin%2C%20J.-R.%2C%20Robitschek%2C%20E.%20J.%2C%20Kasumova%2C%20G.%20G.%2C%20Heyde%2C%20A.%2C%20Shi%2C%20A.%2C%20Kraya%2C%20A.%2C%20Zhang%2C%20G.%2C%20Moll%2C%20T.%2C%20Frederick%2C%20D.%20T.%2C%20Chen%2C%20Y.-A.%2C%20Wang%2C%20S.%2C%20Schapiro%2C%20D.%2C%20Ho%2C%20L.-L.%2C%20Bi%2C%20K.%2C%20Sahu%2C%20A.%2C%20Mei%2C%20S.%2C%20Miao%2C%20B.%2C%20Sharova%2C%20T.%2C%20%26%23x2026%3B%20Boland%2C%20G.%20M.%20%282021%29.%20Evolution%20of%20delayed%20resistance%20to%20immunotherapy%20in%20a%20melanoma%20responder.%20%3Ci%3ENature%20Medicine%3C%5C%2Fi%3E%2C%20%3Ci%3E27%3C%5C%2Fi%3E%286%29%2C%20985%26%23x2013%3B992.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41591-021-01331-8%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41591-021-01331-8%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Evolution%20of%20delayed%20resistance%20to%20immunotherapy%20in%20a%20melanoma%20responder%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jia-Ren%22%2C%22lastName%22%3A%22Lin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Emily%20J.%22%2C%22lastName%22%3A%22Robitschek%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gyulnara%20G.%22%2C%22lastName%22%3A%22Kasumova%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alex%22%2C%22lastName%22%3A%22Heyde%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alvin%22%2C%22lastName%22%3A%22Shi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Adam%22%2C%22lastName%22%3A%22Kraya%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gao%22%2C%22lastName%22%3A%22Zhang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tabea%22%2C%22lastName%22%3A%22Moll%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Dennie%20T.%22%2C%22lastName%22%3A%22Frederick%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Yu-An%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shu%22%2C%22lastName%22%3A%22Wang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Denis%22%2C%22lastName%22%3A%22Schapiro%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Li-Lun%22%2C%22lastName%22%3A%22Ho%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kevin%22%2C%22lastName%22%3A%22Bi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Avinash%22%2C%22lastName%22%3A%22Sahu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shaolin%22%2C%22lastName%22%3A%22Mei%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benchun%22%2C%22lastName%22%3A%22Miao%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tatyana%22%2C%22lastName%22%3A%22Sharova%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christopher%22%2C%22lastName%22%3A%22Alvarez-Breckenridge%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jackson%20H.%22%2C%22lastName%22%3A%22Stocking%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tommy%22%2C%22lastName%22%3A%22Kim%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Riley%22%2C%22lastName%22%3A%22Fadden%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Donald%22%2C%22lastName%22%3A%22Lawrence%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mai%20P.%22%2C%22lastName%22%3A%22Hoang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Daniel%20P.%22%2C%22lastName%22%3A%22Cahill%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mohsen%22%2C%22lastName%22%3A%22Malehmir%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Martin%20A.%22%2C%22lastName%22%3A%22Nowak%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Priscilla%20K.%22%2C%22lastName%22%3A%22Brastianos%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christine%20G.%22%2C%22lastName%22%3A%22Lian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Eytan%22%2C%22lastName%22%3A%22Ruppin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benjamin%22%2C%22lastName%22%3A%22Izar%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Meenhard%22%2C%22lastName%22%3A%22Herlyn%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Eliezer%20M.%22%2C%22lastName%22%3A%22Van%20Allen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Katherine%22%2C%22lastName%22%3A%22Nathanson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Keith%20T.%22%2C%22lastName%22%3A%22Flaherty%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ryan%20J.%22%2C%22lastName%22%3A%22Sullivan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Manolis%22%2C%22lastName%22%3A%22Kellis%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Genevieve%20M.%22%2C%22lastName%22%3A%22Boland%22%7D%5D%2C%22abstractNote%22%3A%22Despite%20initial%20responses1-3%2C%20most%20melanoma%20patients%20develop%20resistance4%20to%20immune%20checkpoint%20blockade%20%28ICB%29.%20To%20understand%20the%20evolution%20of%20resistance%2C%20we%20studied%2037%20tumor%20samples%20over%209%20years%20from%20a%20patient%20with%20metastatic%20melanoma%20with%20complete%20clinical%20response%20to%20ICB%20followed%20by%20delayed%20recurrence%20and%20death.%20Phylogenetic%20analysis%20revealed%20co-evolution%20of%20seven%20lineages%20with%20multiple%20convergent%2C%20but%20independent%20resistance-associated%20alterations.%20All%20recurrent%20tumors%20emerged%20from%20a%20lineage%20characterized%20by%20loss%20of%20chromosome%2015q%2C%20with%20post-treatment%20clones%20acquiring%20additional%20genomic%20driver%20events.%20Deconvolution%20of%20bulk%20RNA%20sequencing%20and%20highly%20multiplexed%20immunofluorescence%20%28t-CyCIF%29%20revealed%20differences%20in%20immune%20composition%20among%20different%20lineages.%20Imaging%20revealed%20a%20vasculogenic%20mimicry%20phenotype%20in%20NGFRhi%20tumor%20cells%20with%20high%20PD-L1%20expression%20in%20close%20proximity%20to%20immune%20cells.%20Rapid%20autopsy%20demonstrated%20two%20distinct%20NGFR%20spatial%20patterns%20with%20high%20polarity%20and%20proximity%20to%20immune%20cells%20in%20subcutaneous%20tumors%20versus%20a%20diffuse%20spatial%20pattern%20in%20lung%20tumors%2C%20suggesting%20different%20roles%20of%20this%20neural-crest-like%20program%20in%20different%20tumor%20microenvironments.%20Broadly%2C%20this%20study%20establishes%20a%20high-resolution%20map%20of%20the%20evolutionary%20dynamics%20of%20resistance%20to%20ICB%2C%20characterizes%20a%20de-differentiated%20neural-crest%20tumor%20population%20in%20melanoma%20immunotherapy%20resistance%20and%20describes%20site-specific%20differences%20in%20tumor-immune%20interactions%20via%20longitudinal%20analysis%20of%20a%20patient%20with%20melanoma%20with%20an%20unusual%20clinical%20course.%22%2C%22date%22%3A%222021-06%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1038%5C%2Fs41591-021-01331-8%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2233941922%22%2C%22PMCID%22%3A%22PMC8474080%22%2C%22ISSN%22%3A%221546-170X%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222024-10-25T21%3A30%3A18Z%22%7D%7D%2C%7B%22key%22%3A%22QHNCA5VK%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Gerosa%20et%20al.%22%2C%22parsedDate%22%3A%222020-11-18%22%2C%22numChildren%22%3A13%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EGerosa%2C%20L.%2C%20Chidley%2C%20C.%2C%20Fr%26%23xF6%3Bhlich%2C%20F.%2C%20Sanchez%2C%20G.%2C%20Lim%2C%20S.%20K.%2C%20Muhlich%2C%20J.%2C%20Chen%2C%20J.-Y.%2C%20Vallabhaneni%2C%20S.%2C%20Baker%2C%20G.%20J.%2C%20Schapiro%2C%20D.%2C%20Atanasova%2C%20M.%20I.%2C%20Chylek%2C%20L.%20A.%2C%20Shi%2C%20T.%2C%20Yi%2C%20L.%2C%20Nicora%2C%20C.%20D.%2C%20Claas%2C%20A.%2C%20Ng%2C%20T.%20S.%20C.%2C%20Kohler%2C%20R.%20H.%2C%20Lauffenburger%2C%20D.%20A.%2C%20%26%23x2026%3B%20Sorger%2C%20P.%20K.%20%282020%29.%20Receptor-driven%20ERK%20pulses%20reconfigure%20MAPK%20signaling%20and%20enable%20persistence%20of%20drug-adapted%20BRAF-mutant%20melanoma%20cells.%20%3Ci%3ECell%20Systems%3C%5C%2Fi%3E%2C%20%3Ci%3E11%3C%5C%2Fi%3E%285%29%2C%20478-494.e9.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.cels.2020.10.002%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.cels.2020.10.002%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Receptor-driven%20ERK%20pulses%20reconfigure%20MAPK%20signaling%20and%20enable%20persistence%20of%20drug-adapted%20BRAF-mutant%20melanoma%20cells%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Luca%22%2C%22lastName%22%3A%22Gerosa%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christopher%22%2C%22lastName%22%3A%22Chidley%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Fabian%22%2C%22lastName%22%3A%22Fr%5Cu00f6hlich%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gabriela%22%2C%22lastName%22%3A%22Sanchez%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sang%20Kyun%22%2C%22lastName%22%3A%22Lim%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jeremy%22%2C%22lastName%22%3A%22Muhlich%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jia-Yun%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sreeram%22%2C%22lastName%22%3A%22Vallabhaneni%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gregory%20J.%22%2C%22lastName%22%3A%22Baker%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Denis%22%2C%22lastName%22%3A%22Schapiro%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mariya%20I.%22%2C%22lastName%22%3A%22Atanasova%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lily%20A.%22%2C%22lastName%22%3A%22Chylek%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tujin%22%2C%22lastName%22%3A%22Shi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Lian%22%2C%22lastName%22%3A%22Yi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Carrie%20D.%22%2C%22lastName%22%3A%22Nicora%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Allison%22%2C%22lastName%22%3A%22Claas%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Thomas%20S.%20C.%22%2C%22lastName%22%3A%22Ng%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Rainer%20H.%22%2C%22lastName%22%3A%22Kohler%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Douglas%20A.%22%2C%22lastName%22%3A%22Lauffenburger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ralph%22%2C%22lastName%22%3A%22Weissleder%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Miles%20A.%22%2C%22lastName%22%3A%22Miller%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Wei-Jun%22%2C%22lastName%22%3A%22Qian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22H.%20Steven%22%2C%22lastName%22%3A%22Wiley%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%5D%2C%22abstractNote%22%3A%22Targeted%20inhibition%20of%20oncogenic%20pathways%20can%20be%20highly%20effective%20in%20halting%20the%20rapid%20growth%20of%20tumors%20but%20often%20leads%20to%20the%20emergence%20of%20slowly%20dividing%20persister%20cells%2C%20which%20constitute%20a%20reservoir%20for%20the%20selection%20of%20drug-resistant%20clones.%20In%20BRAFV600E%20melanomas%2C%20RAF%20and%20MEK%20inhibitors%20efficiently%20block%20oncogenic%20signaling%2C%20but%20persister%20cells%20emerge.%20Here%2C%20we%20show%20that%20persister%20cells%20escape%20drug-induced%20cell-cycle%20arrest%20via%20brief%2C%20sporadic%20ERK%20pulses%20generated%20by%20transmembrane%20receptors%20and%20growth%20factors%20operating%20in%20an%20autocrine%5C%2Fparacrine%20manner.%20Quantitative%20proteomics%20and%20computational%20modeling%20show%20that%20ERK%20pulsing%20is%20enabled%20by%20rewiring%20of%20mitogen-activated%20protein%20kinase%20%28MAPK%29%20signaling%3A%20from%20an%20oncogenic%20BRAFV600E%20monomer-driven%20configuration%20that%20is%20drug%20sensitive%20to%20a%20receptor-driven%20configuration%20that%20involves%20Ras-GTP%20and%20RAF%20dimers%20and%20is%20highly%20resistant%20to%20RAF%20and%20MEK%20inhibitors.%20Altogether%2C%20this%20work%20shows%20that%20pulsatile%20MAPK%20activation%20by%20factors%20in%20the%20microenvironment%20generates%20a%20persistent%20population%20of%20melanoma%20cells%20that%20rewires%20MAPK%20signaling%20to%20sustain%20non-genetic%20drug%20resistance.%22%2C%22date%22%3A%222020-11-18%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1016%5C%2Fj.cels.2020.10.002%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2233113355%22%2C%22PMCID%22%3A%22PMC8009031%22%2C%22ISSN%22%3A%222405-4720%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222024-10-31T19%3A20%3A47Z%22%7D%7D%2C%7B%22key%22%3A%224X5IUZ8J%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Melms%20et%20al.%22%2C%22parsedDate%22%3A%222020-02-15%22%2C%22numChildren%22%3A7%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EMelms%2C%20J.%20C.%2C%20Vallabhaneni%2C%20S.%2C%20Mills%2C%20C.%20E.%2C%20Yapp%2C%20C.%2C%20Chen%2C%20J.-Y.%2C%20Morelli%2C%20E.%2C%20Waszyk%2C%20P.%2C%20Kumar%2C%20S.%2C%20Deming%2C%20D.%2C%20Moret%2C%20N.%2C%20Rodriguez%2C%20S.%2C%20Subramanian%2C%20K.%2C%20Rogava%2C%20M.%2C%20Cartwright%2C%20A.%20N.%20R.%2C%20Luoma%2C%20A.%2C%20Mei%2C%20S.%2C%20Brinker%2C%20T.%20J.%2C%20Miller%2C%20D.%20M.%2C%20Spektor%2C%20A.%2C%20%26%23x2026%3B%20Izar%2C%20B.%20%282020%29.%20Inhibition%20of%20haspin%20kinase%20promotes%20cell-intrinsic%20and%20extrinsic%20antitumor%20activity.%20%3Ci%3ECancer%20Research%3C%5C%2Fi%3E%2C%20%3Ci%3E80%3C%5C%2Fi%3E%284%29%2C%20798%26%23x2013%3B810.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1158%5C%2F0008-5472.CAN-19-2330%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1158%5C%2F0008-5472.CAN-19-2330%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Inhibition%20of%20haspin%20kinase%20promotes%20cell-intrinsic%20and%20extrinsic%20antitumor%20activity%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Johannes%20C.%22%2C%22lastName%22%3A%22Melms%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sreeram%22%2C%22lastName%22%3A%22Vallabhaneni%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Caitlin%20E.%22%2C%22lastName%22%3A%22Mills%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Clarence%22%2C%22lastName%22%3A%22Yapp%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jia-Yun%22%2C%22lastName%22%3A%22Chen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Eugenio%22%2C%22lastName%22%3A%22Morelli%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Patricia%22%2C%22lastName%22%3A%22Waszyk%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sushil%22%2C%22lastName%22%3A%22Kumar%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Derrick%22%2C%22lastName%22%3A%22Deming%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nienke%22%2C%22lastName%22%3A%22Moret%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Steven%22%2C%22lastName%22%3A%22Rodriguez%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kartik%22%2C%22lastName%22%3A%22Subramanian%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Meri%22%2C%22lastName%22%3A%22Rogava%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Adam%20N.%20R.%22%2C%22lastName%22%3A%22Cartwright%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Adrienne%22%2C%22lastName%22%3A%22Luoma%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shaolin%22%2C%22lastName%22%3A%22Mei%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Titus%20J.%22%2C%22lastName%22%3A%22Brinker%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%20M.%22%2C%22lastName%22%3A%22Miller%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alexander%22%2C%22lastName%22%3A%22Spektor%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Dirk%22%2C%22lastName%22%3A%22Schadendorf%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nicolo%22%2C%22lastName%22%3A%22Riggi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kai%20W.%22%2C%22lastName%22%3A%22Wucherpfennig%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benjamin%22%2C%22lastName%22%3A%22Izar%22%7D%5D%2C%22abstractNote%22%3A%22Patients%20with%20melanoma%20resistant%20to%20RAF%5C%2FMEK%20inhibitors%20%28RMi%29%20are%20frequently%20resistant%20to%20other%20therapies%2C%20such%20as%20immune%20checkpoint%20inhibitors%20%28ICI%29%2C%20and%20individuals%20succumb%20to%20their%20disease.%20New%20drugs%20that%20control%20tumor%20growth%20and%20favorably%20modulate%20the%20immune%20environment%20are%20therefore%20needed.%20We%20report%20that%20the%20small-molecule%20CX-6258%20has%20potent%20activity%20against%20both%20RMi-sensitive%20%28RMS%29%20and%20-resistant%20%28RMR%29%20melanoma%20cell%20lines.%20Haspin%20kinase%20%28HASPIN%29%20was%20identified%20as%20a%20target%20of%20CX-6258.%20HASPIN%20inhibition%20resulted%20in%20reduced%20proliferation%2C%20frequent%20formation%20of%20micronuclei%2C%20recruitment%20of%20cGAS%2C%20and%20activation%20of%20the%20cyclic%20GMP-AMP%20synthase%20%28cGAS%29-stimulator%20of%20interferon%20genes%20%28STING%29%20pathway.%20In%20murine%20models%2C%20CX-6258%20induced%20a%20potent%20cGAS-dependent%20type-I%20IFN%20response%20in%20tumor%20cells%2C%20increased%20IFN%5Cu03b3-producing%20CD8%2B%20T%20cells%2C%20and%20reduced%20Treg%20frequency%20in%20vivo.%20HASPIN%20was%20more%20strongly%20expressed%20in%20malignant%20compared%20with%20healthy%20tissue%20and%20its%20inhibition%20by%20CX-6258%20had%20minimal%20toxicity%20in%20ex%20vivo-expanded%20human%20tumor-infiltrating%20lymphocytes%20%28TIL%29%2C%20proliferating%20TILs%2C%20and%20in%20vitro%20differentiated%20neurons%2C%20suggesting%20a%20potential%20therapeutic%20index%20for%20anticancer%20therapy.%20Furthermore%2C%20the%20activity%20of%20CX-6258%20was%20validated%20in%20several%20Ewing%20sarcoma%20and%20multiple%20myeloma%20cell%20lines.%20Thus%2C%20HASPIN%20inhibition%20may%20overcome%20drug%20resistance%20in%20melanoma%2C%20modulate%20the%20immune%20environment%2C%20and%20target%20a%20vulnerability%20in%20different%20cancer%20lineages.%20SIGNIFICANCE%3A%20HASPIN%20inhibition%20by%20CX-6258%20is%20a%20novel%20and%20potent%20strategy%20for%20RAF%5C%2FMEK%20inhibitor-resistant%20melanoma%20and%20potentially%20other%20tumor%20types.%20HASPIN%20inhibition%20has%20direct%20antitumor%20activity%20and%20induces%20a%20favorable%20immune%20microenvironment.%22%2C%22date%22%3A%22Feb%2015%2C%202020%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1158%5C%2F0008-5472.CAN-19-2330%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2231882401%22%2C%22PMCID%22%3A%22PMC7029677%22%2C%22ISSN%22%3A%221538-7445%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-01-17T02%3A23%3A16Z%22%7D%7D%2C%7B%22key%22%3A%22SV2HAGDH%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Jerby-Arnon%20et%20al.%22%2C%22parsedDate%22%3A%222018-11-01%22%2C%22numChildren%22%3A4%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EJerby-Arnon%2C%20L.%2C%20Shah%2C%20P.%2C%20Cuoco%2C%20M.%20S.%2C%20Rodman%2C%20C.%2C%20Su%2C%20M.-J.%2C%20Melms%2C%20J.%20C.%2C%20Leeson%2C%20R.%2C%20Kanodia%2C%20A.%2C%20Mei%2C%20S.%2C%20Lin%2C%20J.-R.%2C%20Wang%2C%20S.%2C%20Rabasha%2C%20B.%2C%20Liu%2C%20D.%2C%20Zhang%2C%20G.%2C%20Margolais%2C%20C.%2C%20Ashenberg%2C%20O.%2C%20Ott%2C%20P.%20A.%2C%20Buchbinder%2C%20E.%20I.%2C%20Haq%2C%20R.%2C%20%26%23x2026%3B%20Regev%2C%20A.%20%282018%29.%20A%20cancer%20cell%20program%20promotes%20T%20cell%20exclusion%20and%20resistance%20to%20checkpoint%20blockade.%20%3Ci%3ECell%3C%5C%2Fi%3E%2C%20%3Ci%3E175%3C%5C%2Fi%3E%284%29%2C%20984-997.e24.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.cell.2018.09.006%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1016%5C%2Fj.cell.2018.09.006%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22A%20cancer%20cell%20program%20promotes%20T%20cell%20exclusion%20and%20resistance%20to%20checkpoint%20blockade%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Livnat%22%2C%22lastName%22%3A%22Jerby-Arnon%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Parin%22%2C%22lastName%22%3A%22Shah%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Michael%20S.%22%2C%22lastName%22%3A%22Cuoco%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Christopher%22%2C%22lastName%22%3A%22Rodman%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mei-Ju%22%2C%22lastName%22%3A%22Su%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Johannes%20C.%22%2C%22lastName%22%3A%22Melms%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Rachel%22%2C%22lastName%22%3A%22Leeson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Abhay%22%2C%22lastName%22%3A%22Kanodia%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shaolin%22%2C%22lastName%22%3A%22Mei%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jia-Ren%22%2C%22lastName%22%3A%22Lin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shu%22%2C%22lastName%22%3A%22Wang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bokang%22%2C%22lastName%22%3A%22Rabasha%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%22%2C%22lastName%22%3A%22Liu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gao%22%2C%22lastName%22%3A%22Zhang%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Claire%22%2C%22lastName%22%3A%22Margolais%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Orr%22%2C%22lastName%22%3A%22Ashenberg%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Patrick%20A.%22%2C%22lastName%22%3A%22Ott%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elizabeth%20I.%22%2C%22lastName%22%3A%22Buchbinder%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Rizwan%22%2C%22lastName%22%3A%22Haq%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22F.%20Stephen%22%2C%22lastName%22%3A%22Hodi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Genevieve%20M.%22%2C%22lastName%22%3A%22Boland%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Ryan%20J.%22%2C%22lastName%22%3A%22Sullivan%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Dennie%20T.%22%2C%22lastName%22%3A%22Frederick%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benchun%22%2C%22lastName%22%3A%22Miao%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Tabea%22%2C%22lastName%22%3A%22Moll%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Keith%20T.%22%2C%22lastName%22%3A%22Flaherty%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Meenhard%22%2C%22lastName%22%3A%22Herlyn%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Russell%20W.%22%2C%22lastName%22%3A%22Jenkins%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Rohit%22%2C%22lastName%22%3A%22Thummalapalli%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Monika%20S.%22%2C%22lastName%22%3A%22Kowalczyk%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Israel%22%2C%22lastName%22%3A%22Ca%5Cu00f1adas%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bastian%22%2C%22lastName%22%3A%22Schilling%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Adam%20N.%20R.%22%2C%22lastName%22%3A%22Cartwright%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Adrienne%20M.%22%2C%22lastName%22%3A%22Luoma%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Shruti%22%2C%22lastName%22%3A%22Malu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Patrick%22%2C%22lastName%22%3A%22Hwu%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Chantale%22%2C%22lastName%22%3A%22Bernatchez%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Marie-Andr%5Cu00e9e%22%2C%22lastName%22%3A%22Forget%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22David%20A.%22%2C%22lastName%22%3A%22Barbie%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alex%20K.%22%2C%22lastName%22%3A%22Shalek%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Itay%22%2C%22lastName%22%3A%22Tirosh%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Kai%22%2C%22lastName%22%3A%22Wucherpfennig%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Eliezer%20M.%22%2C%22lastName%22%3A%22Van%20Allen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Dirk%22%2C%22lastName%22%3A%22Schadendorf%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Bruce%20E.%22%2C%22lastName%22%3A%22Johnson%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Asaf%22%2C%22lastName%22%3A%22Rotem%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Orit%22%2C%22lastName%22%3A%22Rozenblatt-Rosen%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Levi%20A.%22%2C%22lastName%22%3A%22Garraway%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Charles%20H.%22%2C%22lastName%22%3A%22Yoon%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benjamin%22%2C%22lastName%22%3A%22Izar%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Aviv%22%2C%22lastName%22%3A%22Regev%22%7D%5D%2C%22abstractNote%22%3A%22Immune%20checkpoint%20inhibitors%20%28ICIs%29%20produce%20durable%20responses%20in%20some%20melanoma%20patients%2C%20but%20many%20patients%20derive%20no%20clinical%20benefit%2C%20and%20the%5Cu00a0molecular%20underpinnings%20of%20such%20resistance%20remain%5Cu00a0elusive.%20Here%2C%20we%20leveraged%20single-cell%20RNA%20sequencing%20%28scRNA-seq%29%20from%2033%20melanoma%20tumors%20and%20computational%20analyses%20to%20interrogate%20malignant%20cell%20states%20that%20promote%20immune%20evasion.%20We%20identified%20a%20resistance%20program%20expressed%20by%20malignant%20cells%20that%20is%20associated%20with%20T%5Cu00a0cell%20exclusion%20and%20immune%20evasion.%20The%20program%20is%20expressed%20prior%20to%20immunotherapy%2C%20characterizes%20cold%20niches%20in%20situ%2C%20and%20predicts%20clinical%20responses%20to%20anti-PD-1%20therapy%20in%20an%20independent%20cohort%20of%20112%20melanoma%20patients.%20CDK4%5C%2F6-inhibition%20represses%20this%20program%20in%20individual%20malignant%20cells%2C%20induces%20senescence%2C%20and%20reduces%20melanoma%20tumor%20outgrowth%20in%20mouse%20models%20in%5Cu00a0vivo%20when%20given%20in%20combination%20with%20immunotherapy.%20Our%20study%20provides%20a%20high-resolution%20landscape%20of%20ICI-resistant%20cell%20states%2C%20identifies%20clinically%20predictive%20signatures%2C%20and%20suggests%20new%20therapeutic%20strategies%20to%20overcome%20immunotherapy%20resistance.%22%2C%22date%22%3A%222018-11-01%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.1016%5C%2Fj.cell.2018.09.006%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2230388455%22%2C%22PMCID%22%3A%22PMC6410377%22%2C%22ISSN%22%3A%221097-4172%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-12-17T14%3A50%3A53Z%22%7D%7D%2C%7B%22key%22%3A%22R2S29B3U%22%2C%22library%22%3A%7B%22id%22%3A2576724%7D%2C%22meta%22%3A%7B%22lastModifiedByUser%22%3A%7B%22id%22%3A6889081%2C%22username%22%3A%22arenasg%22%2C%22name%22%3A%22%22%2C%22links%22%3A%7B%22alternate%22%3A%7B%22href%22%3A%22https%3A%5C%2F%5C%2Fwww.zotero.org%5C%2Farenasg%22%2C%22type%22%3A%22text%5C%2Fhtml%22%7D%7D%7D%2C%22creatorSummary%22%3A%22Fallahi-Sichani%20et%20al.%22%2C%22parsedDate%22%3A%222017-01-09%22%2C%22numChildren%22%3A6%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EFallahi-Sichani%2C%20M.%2C%20Becker%2C%20V.%2C%20Izar%2C%20B.%2C%20Baker%2C%20G.%20J.%2C%20Lin%2C%20J.-R.%2C%20Boswell%2C%20S.%20A.%2C%20Shah%2C%20P.%2C%20Rotem%2C%20A.%2C%20Garraway%2C%20L.%20A.%2C%20%26amp%3B%20Sorger%2C%20P.%20K.%20%282017%29.%20Adaptive%20resistance%20of%20melanoma%20cells%20to%20RAF%20inhibition%20via%20reversible%20induction%20of%20a%20slowly%20dividing%20de-differentiated%20state.%20%3Ci%3EMolecular%20Systems%20Biology%3C%5C%2Fi%3E%2C%20%3Ci%3E13%3C%5C%2Fi%3E%281%29%2C%20905.%20%3Ca%20class%3D%27zp-DOIURL%27%20target%3D%27_blank%27%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.15252%5C%2Fmsb.20166796%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.15252%5C%2Fmsb.20166796%3C%5C%2Fa%3E%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Adaptive%20resistance%20of%20melanoma%20cells%20to%20RAF%20inhibition%20via%20reversible%20induction%20of%20a%20slowly%20dividing%20de-differentiated%20state%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mohammad%22%2C%22lastName%22%3A%22Fallahi-Sichani%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Verena%22%2C%22lastName%22%3A%22Becker%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Benjamin%22%2C%22lastName%22%3A%22Izar%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Gregory%20J.%22%2C%22lastName%22%3A%22Baker%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Jia-Ren%22%2C%22lastName%22%3A%22Lin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sarah%20A.%22%2C%22lastName%22%3A%22Boswell%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Parin%22%2C%22lastName%22%3A%22Shah%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Asaf%22%2C%22lastName%22%3A%22Rotem%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Levi%20A.%22%2C%22lastName%22%3A%22Garraway%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Peter%20K.%22%2C%22lastName%22%3A%22Sorger%22%7D%5D%2C%22abstractNote%22%3A%22Treatment%20of%20BRAF-mutant%20melanomas%20with%20MAP%20kinase%20pathway%20inhibitors%20is%20paradigmatic%20of%20the%20promise%20of%20precision%20cancer%20therapy%20but%20also%20highlights%20problems%20with%20drug%20resistance%20that%20limit%20patient%20benefit.%20We%20use%20live-cell%20imaging%2C%20single-cell%20analysis%2C%20and%20molecular%20profiling%20to%20show%20that%20exposure%20of%20tumor%20cells%20to%20RAF%5C%2FMEK%20inhibitors%20elicits%20a%20heterogeneous%20response%20in%20which%20some%20cells%20die%2C%20some%20arrest%2C%20and%20the%20remainder%20adapt%20to%20drug.%20Drug-adapted%20cells%20up-regulate%20markers%20of%20the%20neural%20crest%20%28e.g.%2C%20NGFR%29%2C%20a%20melanocyte%20precursor%2C%20and%20grow%20slowly.%20This%20phenotype%20is%20transiently%20stable%2C%20reverting%20to%20the%20drug-na%5Cu00efve%20state%20within%209%5Cu00a0days%20of%20drug%20withdrawal.%20Transcriptional%20profiling%20of%20cell%20lines%20and%20human%20tumors%20implicates%20a%20c-Jun%5C%2FECM%5C%2FFAK%5C%2FSrc%20cascade%20in%20de-differentiation%20in%20about%20one-third%20of%20cell%20lines%20studied%3B%20drug-induced%20changes%20in%20c-Jun%20and%20NGFR%20levels%20are%20also%20observed%20in%20xenograft%20and%20human%20tumors.%20Drugs%20targeting%20the%20c-Jun%5C%2FECM%5C%2FFAK%5C%2FSrc%20cascade%20as%20well%20as%20BET%20bromodomain%20inhibitors%20increase%20the%20maximum%20effect%20%28Emax%29%20of%20RAF%5C%2FMEK%20kinase%20inhibitors%20by%20promoting%20cell%20killing.%20Thus%2C%20analysis%20of%20reversible%20drug%20resistance%20at%20a%20single-cell%20level%20identifies%20signaling%20pathways%20and%20inhibitory%20drugs%20missed%20by%20assays%20that%20focus%20on%20cell%20populations.%22%2C%22date%22%3A%222017-01-09%22%2C%22section%22%3A%22%22%2C%22partNumber%22%3A%22%22%2C%22partTitle%22%3A%22%22%2C%22DOI%22%3A%2210.15252%5C%2Fmsb.20166796%22%2C%22citationKey%22%3A%22%22%2C%22url%22%3A%22%22%2C%22PMID%22%3A%2228069687%22%2C%22PMCID%22%3A%22PMC5248573%22%2C%22ISSN%22%3A%221744-4292%22%2C%22language%22%3A%22eng%22%2C%22collections%22%3A%5B%22IXMHRBF6%22%5D%2C%22dateModified%22%3A%222025-12-17T16%3A56%3A14Z%22%7D%7D%5D%7D
Zimmerman, M. P., Huang, A. C., Cox, E. K., Al Abosy, R., Chong, W. L., Bastian, A. G., Vietor, K., Choutri, Y., Collier, J., Zhabotynsky, V., Wang, H., Fung, M., Weiss, S. A., Robitschek, E. J., Lin, J.-R., Vallius, T., Pant, S., Sorger, P. K., Hugo, W., … Miller, B. C. (2026).
Harnessing Inflammatory Monocytes to Overcome Resistance to Anti-PD-1 Immunotherapy. bioRxiv.
https://doi.org/10.64898/2026.02.05.704029
Weems, A. D., Islam, M. T., Borges, H., Yapp, C., Perez-Castro, L., Nogueira, P., Lin, J., Maliga, Z., Lewis, A. J., Kutter, C., Mannino, M., Vallius, T., Santagata, S., Sorger, P. K., Conacci-Sorrell, M., Dean, K. M., & Danuser, G. M. (2026).
In vivo evidence for bleb-induced survival signaling in metastatic melanoma. Cancer Biology.
https://doi.org/10.64898/2026.01.05.697601
Rapisuwon, S., Slingluff, C. L., Wargo, J. A., Sullivan, R. J., Izar, B., Lin, J.-R., Mauldin, I. S., Olson, W. C., Tran, C. A., Schwartzman, G. H., Gibney, G. T., Al-Refaie, W., & Atkins, M. B. (2026). Effects of Vemurafenib ± Cobimetinib on Intratumoral and Host Immunity in Patients With BRAFV600 Mutant Melanoma: Implications for Combination With Immunotherapy.
Cancer Medicine,
15(1), e71526.
https://doi.org/10.1002/cam4.71526
Shi, Y., Maliga, Z., Vallius, T., Pant, S. M., Pelletier, R., Kobs, B., Solanky, P., He, Y., Van Allen, E., Santagata, S., Ott, P., Lian, C. G., Buchbinder, E., Liu, D., & Sorger, P. K. (2025).
Mechanisms of tumor persistence in metastatic melanoma following successful immunotherapy. bioRxiv.
https://doi.org/10.64898/2025.12.11.692633
Knight, A. D., Robitschek, E. J., Lin, J.-R., Frederick, D. T., Shi, A., Larque, A. B., Miao, B., Raghavan, R. S., Sharova, T., Shin, J. H., Sorger, P., Kellis, M., Flaherty, K. T., Hacohen, N., Boland, G. M., Chebib, I., Liu, D., Sullivan, R. J., & Mehta, A. (2025).
Melanoma to rhabdomyosarcoma plasticity in the setting of immunotherapy. medRxiv. medRxiv.
https://doi.org/10.1101/2025.10.31.25338685
Ludin, A., Stirtz, G. L., Tal, A., Nirmal, A. J., Pfaff, K. L., Manos, M., Besson, N., Eskndir, N., Porter, B., Jones, S. M., Faulkner, H. M., Gong, Q., Liu, S., Barrera, I., Wu, L., Pessoa Rodrigues, C., Sahu, A., Jerison, E., Alessi, J. V., … Zon, L. I. (2025). CRATER tumor niches facilitate CD8+ T cell engagement and correspond with immunotherapy success.
Cell, S0092-8674(25)01089-X.
https://doi.org/10.1016/j.cell.2025.09.021
Tarantino, G., Zaremba, A., Vallius, T., Woodnorth, M., Hua, Y., Pelletier, R., Lopez Leon, M., Shi, Y., Maliga, Z., Makhzami, S., Aprati, T. J., Karlas, B., Glutsch, V., Schilling, B., Hassel, J., Berking, C., Utikal, J., Meier, F., Meiss, F., … Schadendorf, D. (2025).
Multiomic profiling of a unique in-transit melanoma cohort identifies melanoma differentiation as predictor of tumor progression and therapy response. bioRxiv.
https://doi.org/10.1101/2025.10.01.679282
Yapp, C., Nirmal, A. J., Zhou, F., Wong, A. Y. H., Tefft, J. B., Lu, Y. D., Shang, Z., Maliga, Z., Llopis, P. M., Murphy, G. F., Lian, C. G., Danuser, G., Santagata, S., & Sorger, P. K. (2025). Highly multiplexed 3D profiling of cell states and immune niches in human tumors.
Nature Methods.
https://doi.org/10.1038/s41592-025-02824-x
Vallius, T., Shi, Y., Novikov, E., Pant, S. M., Pelletier, R., Chen, Y.-A., Tefft, J. B., Johnson, A. N., Maliga, Z., Wan, G., Murphy, G., Santagata, S., Semenov, Y. R., Liu, D., Lian, C. G., & Sorger, P. K. (2025).
Spatial determinants of tumor cell dedifferentiation and plasticity in primary cutaneous melanoma. bioRxiv.
https://doi.org/10.1101/2025.06.21.660851
Fang, R., Vallius, T., Zhang, A., Van Cura, D., Alicandri, F., Fischer, G., Draper, E., Xu, S., Pelletier, R., Wang, J., Mandinova, A., Katsyv, I., Sorger, P. K., Murphy, G. F., & Lian, C. G. (2025). PRAME Expression in Melanoma is Negatively Regulated by TET2-Mediated DNA Hydroxymethylation.
Laboratory Investigation; a Journal of Technical Methods and Pathology,
105(5), 104123.
https://doi.org/10.1016/j.labinv.2025.104123
Oka, T., Hasegawa, T., Lee, T., Oliver-Garcia, V. S., Mortaja, M., Azin, M., Horiba, S., Smith, S. S., Khattab, S., Trerice, K. E., Chen, S. T., Semenov, Y. R., & Demehri, S. (2025). Langerhans Cells Directly Interact with Resident T Cells in the Human Epidermis.
JID Innovations: Skin Science from Molecules to Population Health,
5(1), 100324.
https://doi.org/10.1016/j.xjidi.2024.100324
Ma, Y., Tagore, M., Hunter, M. V., Huang, T.-H., Montal, E., Weiss, J. M., Shi, Y., Vallius, T., Sorger, P. K., & White, R. M. (2024).
Restraint of melanoma progression by cells in the local skin environment. Cancer Biology.
https://doi.org/10.1101/2024.08.15.608067
Rogava, M., Aprati, T. J., Chi, W.-Y., Melms, J. C., Hug, C., Davis, S. H., Earlie, E. M., Chung, C., Deshmukh, S. K., Wu, S., Sledge, G., Tang, S., Ho, P., Amin, A. D., Caprio, L., Gurjao, C., Tagore, S., Ngo, B., Lee, M. J., … Izar, B. (2024). Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.
Nature Cancer,
5(3), 433–447.
https://doi.org/10.1038/s43018-023-00704-x
Zhang, X., Pant, S. M., Ritch, C. C., Tang, H.-Y., Shao, H., Dweep, H., Gong, Y.-Y., Brooks, R., Brafford, P., Wolpaw, A. J., Lee, Y., Weeraratna, A., Sehgal, A., Herlyn, M., Kossenkov, A., Speicher, D., Sorger, P. K., Santagata, S., & Dang, C. V. (2024). Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity.
Nature Communications,
15(1), 633.
https://doi.org/10.1038/s41467-024-44778-2
Wan, G., Leung, B. W., DeSimone, M. S., Nguyen, N., Rajeh, A., Collier, M. R., Rashdan, H., Roster, K., Zhou, X., Moseley, C. B., Nirmal, A. J., Pelletier, R. J., Maliga, Z., Marko-Varga, G., Németh, I. B., Tsao, H., Asgari, M. M., Gusev, A., Stagner, A. M., … Semenov, Y. R. (2023). Development and validation of time-to-event models to predict metastatic recurrence of localized cutaneous melanoma.
Journal of the American Academy of Dermatology, S0190-9622(23)02881-5.
https://doi.org/10.1016/j.jaad.2023.08.105
Fröhlich, F., Gerosa, L., Muhlich, J., & Sorger, P. K. (2023). Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance.
Molecular Systems Biology,
19(2), e10988.
https://doi.org/10.15252/msb.202210988
Nirmal, A. J., Maliga, Z., Vallius, T., Quattrochi, B., Chen, A. A., Jacobson, C. A., Pelletier, R. J., Yapp, C., Arias-Camison, R., Chen, Y.-A., Lian, C. G., Murphy, G. F., Santagata, S., & Sorger, P. K. (2022). The spatial landscape of progression and immunoediting in primary melanoma at single-cell resolution.
Cancer Discovery,
12(6), 1518–1541.
https://doi.org/10.1158/2159-8290.CD-21-1357
Hodis, E., Torlai Triglia, E., Kwon, J. Y. H., Biancalani, T., Zakka, L. R., Parkar, S., Hütter, J.-C., Buffoni, L., Delorey, T. M., Phillips, D., Dionne, D., Nguyen, L. T., Schapiro, D., Maliga, Z., Jacobson, C. A., Hendel, A., Rozenblatt-Rosen, O., Mihm, M. C., Garraway, L. A., & Regev, A. (2022). Stepwise-edited, human melanoma models reveal mutations’ effect on tumor and microenvironment.
Science (New York, N.Y.),
376(6592), eabi8175.
https://doi.org/10.1126/science.abi8175
Liu, D., Lin, J.-R., Robitschek, E. J., Kasumova, G. G., Heyde, A., Shi, A., Kraya, A., Zhang, G., Moll, T., Frederick, D. T., Chen, Y.-A., Wang, S., Schapiro, D., Ho, L.-L., Bi, K., Sahu, A., Mei, S., Miao, B., Sharova, T., … Boland, G. M. (2021). Evolution of delayed resistance to immunotherapy in a melanoma responder.
Nature Medicine,
27(6), 985–992.
https://doi.org/10.1038/s41591-021-01331-8
Gerosa, L., Chidley, C., Fröhlich, F., Sanchez, G., Lim, S. K., Muhlich, J., Chen, J.-Y., Vallabhaneni, S., Baker, G. J., Schapiro, D., Atanasova, M. I., Chylek, L. A., Shi, T., Yi, L., Nicora, C. D., Claas, A., Ng, T. S. C., Kohler, R. H., Lauffenburger, D. A., … Sorger, P. K. (2020). Receptor-driven ERK pulses reconfigure MAPK signaling and enable persistence of drug-adapted BRAF-mutant melanoma cells.
Cell Systems,
11(5), 478-494.e9.
https://doi.org/10.1016/j.cels.2020.10.002
Melms, J. C., Vallabhaneni, S., Mills, C. E., Yapp, C., Chen, J.-Y., Morelli, E., Waszyk, P., Kumar, S., Deming, D., Moret, N., Rodriguez, S., Subramanian, K., Rogava, M., Cartwright, A. N. R., Luoma, A., Mei, S., Brinker, T. J., Miller, D. M., Spektor, A., … Izar, B. (2020). Inhibition of haspin kinase promotes cell-intrinsic and extrinsic antitumor activity.
Cancer Research,
80(4), 798–810.
https://doi.org/10.1158/0008-5472.CAN-19-2330
Jerby-Arnon, L., Shah, P., Cuoco, M. S., Rodman, C., Su, M.-J., Melms, J. C., Leeson, R., Kanodia, A., Mei, S., Lin, J.-R., Wang, S., Rabasha, B., Liu, D., Zhang, G., Margolais, C., Ashenberg, O., Ott, P. A., Buchbinder, E. I., Haq, R., … Regev, A. (2018). A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade.
Cell,
175(4), 984-997.e24.
https://doi.org/10.1016/j.cell.2018.09.006
Fallahi-Sichani, M., Becker, V., Izar, B., Baker, G. J., Lin, J.-R., Boswell, S. A., Shah, P., Rotem, A., Garraway, L. A., & Sorger, P. K. (2017). Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state.
Molecular Systems Biology,
13(1), 905.
https://doi.org/10.15252/msb.20166796