{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:27:43Z","timestamp":1768508863401,"version":"3.49.0"},"posted":{"date-parts":[[2023,12,10]]},"group-title":"Cancer Biology","reference-count":88,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Cutaneous melanomas are clinically and histologically heterogeneous. Most display activating mutations in\n                  <jats:italic>Braf<\/jats:italic>\n                  or\n                  <jats:italic>Nras<\/jats:italic>\n                  and complete loss of function of one or more tumor suppressor genes. Mouse models that replicate such mutations produce fast-growing, pigmented tumors. However, mice that combine\n                  <jats:italic>Braf<\/jats:italic>\n                  activation with only heterozygous loss of\n                  <jats:italic>Pten<\/jats:italic>\n                  also produce tumors and, as we show here, in an Albino background this occurs even with\n                  <jats:italic>Braf<\/jats:italic>\n                  activation alone. Such tumors arise rarely, grow slowly, and express low levels of pigmentation genes. The timing of their appearance was consistent with a single step stochastic event, but no evidence could be found that it required\n                  <jats:italic>de novo<\/jats:italic>\n                  mutation, suggesting instead the involvement of an epigenetic transition. Single-cell transcriptomic analysis revealed such tumors to be heterogeneous, including a minor cell type we term LNM (\n                  <jats:underline>L<\/jats:underline>\n                  ow-pigment,\n                  <jats:underline>N<\/jats:underline>\n                  eural- and extracellular\n                  <jats:underline>M<\/jats:underline>\n                  atrix-signature) that displays gene expression resembling \u201cneural crest\u201d-like cell subsets detected in the fast-growing tumors of more heavily-mutated mice, as well as in human biopsy and xenograft samples. We provide evidence that LNM cells pre-exist in normal skin, are expanded by\n                  <jats:italic>Braf<\/jats:italic>\n                  activation, can transition into malignant cells, and persist with malignant cells through multiple rounds of transplantation. We discuss the possibility that LNM cells not only serve as a pre-malignant state in the production of some melanomas, but also as an important intermediate in the development of drug resistance.\n                <\/jats:p>","DOI":"10.1101\/2023.12.08.570336","type":"posted-content","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T01:15:27Z","timestamp":1702257327000},"source":"Crossref","is-referenced-by-count":0,"title":["Uncovering Minimal Pathways in Melanoma Initiation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4844-2073","authenticated-orcid":false,"given":"Hui","family":"Xiao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2264-8372","authenticated-orcid":false,"given":"Jessica","family":"Shiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6391-821X","authenticated-orcid":false,"given":"Chi-Fen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4585-2923","authenticated-orcid":false,"given":"Peijie","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sahil S.","family":"Telang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolando","family":"Ruiz-Vega","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Nie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur D.","family":"Lander","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anand 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