{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T23:01:42Z","timestamp":1775084502469,"version":"3.50.1"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004775","name":"Natural Science Foundation of Gansu Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004775","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016321","name":"First Clinical Medical School, Lanzhou University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100016321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cutaneous melanoma is a highly aggressive malignancy characterized by significant heterogeneity, rapid progression, and variable treatment responses. Understanding the functional diversity of melanoma cells and their interactions with the tumor microenvironment (TME) is crucial for developing effective therapeutic strategies and identifying prognostic biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed comprehensive single-cell RNA sequencing (scRNA-seq) analysis of 70,760 cells from 11 melanoma samples. Data processing was conducted using Seurat v4.3.0 with Harmony integration. Cell-cell communication was inferred using CellChat, and pseudotime trajectory analysis was performed using Monocle 2. A prognostic model was constructed by integrating 10 machine learning algorithms within a leave-one-out cross-validation (LOOCV) framework using the TCGA-SKCM cohort. Experimental validation was performed using immunofluorescence analysis on clinical specimens from seven melanoma patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified seven major cell types and characterized nine distinct melanoma cell subpopulations with unique molecular signatures. Notably, subpopulations Mela4, Mela6, and Mela9 demonstrated significant associations with favorable patient prognosis and exhibited the highest interaction strength with immune cells in the TME. Cell communication analysis revealed that these subpopulations primarily engaged in signaling through MIF-CD74\/CD44\/CXCR4 and MHC-I pathways, with CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells being the predominant signal recipients. Pseudotime trajectory analysis identified critical genes (CYR61, JUN, RHOC) involved in melanoma cell state transitions. Using an integrative machine learning approach, we developed a melanoma cell-associated signature (MRS) comprising 15 genes that achieved a mean C-index of 0.675 across validation cohorts. Furthermore, High EIF5A expression was significantly associated with poor patient outcomes (p &amp;lt; 0.001), Immunofluorescence analysis showing significantly elevated EIF5A expression in melanoma tissues compared to controls (p &amp;lt; 0.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study reveals the functional heterogeneity of melanoma cells and their interactions with the immune microenvironment, identifies key subpopulations, prognostic signatures, and EIF5A as a plausible prognostic biomarker candidate and potential therapeutic target that warrants mechanistic validation in melanoma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1779213","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T22:10:24Z","timestamp":1775081424000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell sequencing reveals the functional heterogeneity of melanoma cells and their crosstalk with the tumor microenvironment"],"prefix":"10.3389","volume":"17","author":[{"given":"Jianxiong","family":"Qiao","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaxia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Qin","sequence":"additional","affiliation":[{"name":"The School of Clinical Medicine, Gansu Medical College","place":["Pingliang, Gansu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peigang","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Second School of Clinical Medicine, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanghang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lihong","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Plastic surgery, Tianjin Stomatological Hospital, School of Medicine, Nankai University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Key Laboratory for Reproductive Medicine and Embryo of Gansu, The First School of Clinical Medicine, The First Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, The Second Hospital & Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1001\/jamadermatol.2022.0160","article-title":"Global burden of cutaneous melanoma in 2020 and projections to 2040","volume":"158","author":"Arnold","year":"2022","journal-title":"JAMA Dermatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"102466","DOI":"10.1016\/j.redox.2022.102466","article-title":"Regulation of CyR61 expression and release by 3-mercaptopyruvate sulfurtransferase in colon cancer cells","volume":"56","author":"Ascen\u00e7\u00e3o","year":"2022","journal-title":"Redox Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1200\/JCO.22.01763","article-title":"Combination dabrafenib and trametinib Versus combination Nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: the DREAMseq Trial-ECOG-ACRIN EA6134","volume":"41","author":"Atkins","year":"2023","journal-title":"J. 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