Specific oncogene activation of the cell of origin in mucosal melanoma.

Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we developed a zebrafish model in which all melanocytes experienced CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only developed from melanocytes lining internal organs, analogous to the location of patient MM. We found that zebrafish MMs had a unique chromatin landscape from cutaneous melanoma. Internal melanocytes could be labeled using a MM-specific transcriptional enhancer. Normal zebrafish internal melanocytes shared a gene expression signature with MMs. Patient and zebrafish MMs have increased migratory neural crest gene and decreased antigen presentation gene expression, consistent with the increased metastatic behavior and decreased immunotherapy sensitivity of MM. Our work suggests the cell state of the originating melanocyte influences the behavior of derived melanomas. Our animal model phenotypically and transcriptionally mimics patient tumors, allowing this model to be used for MM therapeutic discovery.
Competing Interests: Competing interests: L.I.Z. is a founder and stockholder of Fate Therapeutics, CAMP4 Therapeutics, and Scholar Rock. He is a consultant for Celularity. B.J.A. is a shareholder in Syros Pharmaceuticals. E.I.B. serves as a consultant/advisory board member for Pfizer, Werewolf pharma, Merck, Iovance, Sanofi, Xilio, and Novartis.