PUBLICATION
Specific oncogene activation of the cell of origin in mucosal melanoma
- Authors
- Babu, S., Chen, J., Baron, C.S., Sun, K., Robitschek, E., McConnell, A.M., Wu, C., Dedeilia, A., Sade-Feldman, M., Modhurima, R., Manos, M.P., Chen, K.Y., Cox, A.M., Ludwig, C.G., Kellis, M., Buchbinder, E.I., Hacohen, N., Yang, J., Boland, G.M., Abraham, B.J., Liu, D., Zon, L.I., Insco, M.L.
- ID
- ZDB-PUB-250724-9
- Date
- 2025
- Source
- Nature communications 16: 67506750 (Journal)
- Registered Authors
- Babu, Swathy, Zon, Leonard I.
- Keywords
- none
- Datasets
- GEO:GSE270356, GEO:GSE270352, GEO:GSE270354
- MeSH Terms
-
- Melanocytes*/metabolism
- Melanocytes*/pathology
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Gene Expression Regulation, Neoplastic
- PTEN Phosphohydrolase/genetics
- PTEN Phosphohydrolase/metabolism
- Animals
- Oncogenes*/genetics
- Neural Crest/metabolism
- Skin Neoplasms*/genetics
- Skin Neoplasms*/pathology
- Disease Models, Animal
- Humans
- Mucous Membrane*/metabolism
- Mucous Membrane*/pathology
- Melanoma*/genetics
- Melanoma*/metabolism
- Melanoma*/pathology
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
- Cyclin D1/genetics
- Cyclin D1/metabolism
- Chromatin/metabolism
- PubMed
- 40695831 Full text @ Nat. Commun.
Citation
Babu, S., Chen, J., Baron, C.S., Sun, K., Robitschek, E., McConnell, A.M., Wu, C., Dedeilia, A., Sade-Feldman, M., Modhurima, R., Manos, M.P., Chen, K.Y., Cox, A.M., Ludwig, C.G., Kellis, M., Buchbinder, E.I., Hacohen, N., Yang, J., Boland, G.M., Abraham, B.J., Liu, D., Zon, L.I., Insco, M.L. (2025) Specific oncogene activation of the cell of origin in mucosal melanoma. Nature communications. 16:67506750.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping