{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T19:00:26Z","timestamp":1784919626736,"version":"3.55.0"},"reference-count":34,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"30","funder":[{"DOI":"10.13039\/100005190","name":"Melanoma Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005190","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005190","name":"Melanoma Research Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,7,24]]},"abstract":"<jats:p>\n                    Melanomas display distinct transcriptomic states, but it remains unclear how they associate with clinical outcomes. We performed digital spatial RNA profiling (DSP-RNA) of metastatic tumors from patients to investigate how transcriptomic states correlate with melanoma specific survival (MSS) and acral melanoma (AM). We performed DSP-RNA across a tissue microarray constructed from 111 patients with in-transit metastatic melanoma (ITM) diagnosed from 1990 to 2020. Data quality control, noise correction, and normalization yielded high-quality profiles from 105 patients, including 30 (36%) who received immune checkpoint inhibitors and 20 (24%) with AM. We performed principal component (PC) analysis and correlated the results with published gene signatures: The PC1 axis differentiated transitory from undifferentiated melanoma, PC2 reflected immune cell infiltration, PC3 corresponded to stromal cells and neural crest\u2013like melanoma, and PC4 associated with melanocytic melanoma. Across a cohort of treatment-na\u00efve ITM, high expression of the melanocytic state conferred a median MSS difference of 7.72 years (melanocytic \u201chigh\u201d\u00a0=\u00a05.16 years versus \u201clow\u201d\u00a0=\u00a012.88 years, log-rank\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0=\u00a00.0061) and independently associated with poor survival in multivariate analysis. AMs showed higher melanocytic state gene expression compared to nonacral. Findings were validated in external datasets, supporting that the melanocytic state predicts poor prognosis. The melanocytic state is associated with poor prognosis and may be enriched in AM, implying that identifying patients with melanocytic melanoma may be important for therapeutic decisions. Unlike other gene expression predictors proposed for prognostic stratification, the melanocytic state characterizes a biological subtype, suggesting that it may have specific therapeutic vulnerabilities.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aec7394","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T17:58:33Z","timestamp":1784915913000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["The melanocytic transcriptomic state is independently associated with poor overall survival in patients with metastatic melanoma"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5781-7503","authenticated-orcid":true,"given":"Ziyin","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA."},{"name":"Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3249-5330","authenticated-orcid":true,"given":"Kristen E.","family":"Rhodin","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9431-0530","authenticated-orcid":true,"given":"Rami","family":"Al-Rohil","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University North Carolina, at Chapel Hill, Chapel Hill, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2399-4589","authenticated-orcid":true,"given":"Viviana","family":"Geron","sequence":"additional","affiliation":[{"name":"University of Illinois College of Medicine, Chicago, IL, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9282-3415","authenticated-orcid":true,"given":"Arul M.","family":"Chinnaiyan","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA."},{"name":"Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA."},{"name":"Department of Urology, University of Michigan, Ann Arbor, MI, USA."},{"name":"Howard Hughes Medical Institute, Chevy Chase, MD, USA."},{"name":"Department of Pathology, University of Michigan, Ann Arbor, MI, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5127-8545","authenticated-orcid":true,"given":"Margaret H.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6500-9589","authenticated-orcid":true,"given":"Christina V.","family":"Angeles","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7019-1912","authenticated-orcid":true,"given":"Smita K.","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0217-7390","authenticated-orcid":true,"given":"Matthew K.","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA."},{"name":"Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA."},{"name":"Department of Surgery, Duke University, Durham, NC, USA."},{"name":"Department of Pathology, University of Michigan, Ann Arbor, MI, USA."},{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6387-9030","authenticated-orcid":true,"given":"Georgia M.","family":"Beasley","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-018-6513-7"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13174431"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2016.10.018"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.23.7610"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.24.00447"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-3316"},{"key":"e_1_3_2_8_2","first-page":"1478","article-title":"Analysis of melanoma gene expression signatures at the single-cell level uncovers 45-gene signature related to prognosis","volume":"10","author":"Bakr M. N.","year":"2022","unstructured":"M. N. Bakr, H. Takahashi, Y. Kikuchi, Analysis of melanoma gene expression signatures at the single-cell level uncovers 45-gene signature related to prognosis. Biomedicine 10, 1478 (2022).","journal-title":"Biomedicine"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-0427"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21207-2"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.037"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/pcmr.13189"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.044"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0501"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.017"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/bfgp\/elad055"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2024.04.012"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43980-y"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005052"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32738-7"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-3932"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.21105\/joss.06604"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34877-3"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1316"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1922-8"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09967-z"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14143371"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46994-2"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0472-9"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-1529"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06130-4"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2507"},{"key":"e_1_3_2_35_2","doi-asserted-by":"crossref","unstructured":"A. A. Sergushichev An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. bioRxiv 10.1101\/060012 [preprint] (2016); https:\/\/doi.org\/10.1101\/060012.","DOI":"10.1101\/060012"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aec7394","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T18:00:50Z","timestamp":1784916050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aec7394"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":34,"journal-issue":{"issue":"30","published-print":{"date-parts":[[2026,7,24]]}},"alternative-id":["10.1126\/sciadv.aec7394"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aec7394","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]},"assertion":[{"value":"2025-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaec7394"}}