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Although the cell-of-origin is presumed to be epithelial, epidermal localization of MCC is rarely observed, largely because in situ MCC is typically an incidental finding. Nevertheless, a subset of MCC tumors exhibits epidermotropism, wherein tumor cells are present in the epidermis. The behavior of cancer cells is profoundly influenced by the tumor microenvironment and interactions with neighboring cells. Notably, the normal counterparts of the cancer\u2019s cell-of-origin have been shown to attenuate tumor aggressiveness. Thus, epidermotropic MCC presents a unique opportunity to explore the potential role of epidermal microenvironment in modulating tumor cell behavior. While the epidermotropic tumor nests share histological resemblance with their dermal counterparts, their transcriptomic profiles remain unexplored. Here, we employed high-definition spatial and single-cell transcriptomics to dissect the gene expression profiles of epidermotropic MCC cells, comparing them to MCC cells in the tumor core and those adjacent to blood vessels. Notably, epidermotropic MCC cells exhibit a transcriptomic signature reminiscent of cutaneous squamous cell carcinoma, characterized by upregulation of genes encoding keratins, S100A proteins, as well as calmodulin-like proteins 3 and 5. Mechanistically, this keratinocytic differentiation is associated with enhanced p63 activity, leading to the upregulation of PERP. Collectively, our study demonstrates that MCC cells can adopt a keratinocytic differentiation program in response to microenvironmental cues, underscoring the remarkable phenotypic plasticity of this malignancy and the importance of the microenvironment for tumor cell characteristics.<\/jats:p>","DOI":"10.1038\/s41388-025-03608-5","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T15:13:31Z","timestamp":1761232411000},"page":"4615-4625","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["High-resolution spatial transcriptomics uncover epidermal-dermal divergences in Merkel cell carcinoma: spatial context reshapes the gene expression landscape"],"prefix":"10.1038","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6804-8914","authenticated-orcid":false,"given":"Kuan Cheok","family":"Lei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6899-0800","authenticated-orcid":false,"given":"Nalini","family":"Srinivas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3593-7173","authenticated-orcid":false,"given":"Mitalee","family":"Chandra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5055-8422","authenticated-orcid":false,"given":"Vahan","family":"Serobyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9384-6704","authenticated-orcid":false,"given":"Selma","family":"Ugurel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2973-7869","authenticated-orcid":false,"given":"Daniel","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2201-6914","authenticated-orcid":false,"given":"Thibault","family":"Kervarrec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4717-4473","authenticated-orcid":false,"given":"Weng-Onn","family":"Lui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9183-653X","authenticated-orcid":false,"given":"J\u00fcrgen C.","family":"Becker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"3608_CR1","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1007\/s40257-024-00858-z","volume":"25","author":"JC Becker","year":"2024","unstructured":"Becker JC, Stang A, Schrama D, Ugurel S. 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JCB participated in a data safety monitoring or advisory board from ICON Clinical Research and 4SC. SU declares research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, and Novartis; and meeting and travel support from Almirall, Bristol-Myers Squibb, IGEA Clinical Biophysics, Merck Sharp & Dohme, Novartis, Pierre Fabre, and Sun Pharma; outside the submitted work. None of the other authors have reported any conflicts or competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}