Specific oncogene activation of the cell of origin in mucosal melanoma

Swathy Babu, Jiajia Chen, Chloé S. Baron, Kaiwen Sun, Emily Robitschek, Alicia M. McConnell, Constance Wu, Aikaterini Dedeilia, Moshe Sade-Feldman, Rodsy Modhurima, Michael P. Manos, Kevin Y. Chen, Anna M. Cox, Calvin G. Ludwig, Manolis Kellis, Elizabeth I. Buchbinder, Nir Hacohen, Jiekun Yang, Genevieve M. Boland, Brian J. Abraham, David Liu, Leonard I. Zon () and Megan L. Insco ()
Additional contact information
Swathy Babu: Dana-Farber Cancer Institute
Jiajia Chen: Dana-Farber Cancer Institute
Chloé S. Baron: Howard Hughes Medical Institute
Kaiwen Sun: Dana-Farber Cancer Institute
Emily Robitschek: Dana-Farber Cancer Institute
Alicia M. McConnell: Howard Hughes Medical Institute
Constance Wu: Howard Hughes Medical Institute
Aikaterini Dedeilia: MGH Krantz Center for Cancer Research
Moshe Sade-Feldman: MGH Krantz Center for Cancer Research
Rodsy Modhurima: Howard Hughes Medical Institute
Michael P. Manos: Dana-Farber Cancer Institute
Kevin Y. Chen: Howard Hughes Medical Institute
Anna M. Cox: Dana-Farber Cancer Institute
Calvin G. Ludwig: Howard Hughes Medical Institute
Manolis Kellis: Broad Institute of Massachusetts Institute of Technology (MIT)
Elizabeth I. Buchbinder: Dana-Farber Cancer Institute
Nir Hacohen: MGH Krantz Center for Cancer Research
Jiekun Yang: Broad Institute of Massachusetts Institute of Technology (MIT)
Genevieve M. Boland: MGH Krantz Center for Cancer Research
Brian J. Abraham: St. Jude Children’s Research Hospital
David Liu: Dana-Farber Cancer Institute
Leonard I. Zon: Howard Hughes Medical Institute
Megan L. Insco: Dana-Farber Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Mucosal melanoma (MM) is a deadly cancer derived from mucosal melanocytes. To test the consequences of MM genetics, we develop a zebrafish model in which all melanocytes experience CCND1 expression and loss of PTEN and TP53. Surprisingly, melanoma only develops from melanocytes lining internal organs, analogous to the location of patient MM. We find that zebrafish MMs have a unique chromatin landscape from cutaneous melanomas. Internal melanocytes are labeled using a MM-specific transcriptional enhancer. Normal zebrafish internal melanocytes share a gene expression signature with MMs. Patient and zebrafish MMs show increased migratory neural crest and decreased antigen presentation gene expression, consistent with the increased metastatic behavior and decreased immunotherapy sensitivity of MM. Our work suggests that 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. As this is a non-MAPK driven genetically engineered model of melanoma, our work also has implications for the 15% of cutaneous melanoma patients who lack MAPK-driving mutations.

Date: 2025
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DOI: 10.1038/s41467-025-61937-1

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