A preclinical model of malignant peripheral nerve sheath tumor-like is characterized by infiltrating mast cells

Human melanomas exhibit considerable genetic, pathological, and microenvironmental heterogeneity. Genetically engineered mice have successfully been used to model the genomic aberrations contributing to melanoma pathogenesis, but their ability to recapitulate the phenotypic variability of human disease and the complex interactions with the immune system have not been addressed. Here we report the unexpected finding that immune-cell poor pigmented and immunecell rich amelanotic melanomas developed simultaneously in Cdk4R24C mutant mice upon melanocyte-specific conditional activation of oncogenic BrafV600E and a single application of the carcinogen DMBA. Interestingly, amelanotic melanomas showed morphological and molecular features of malignant peripheral nerve sheath tumors (MPNST). A bioinformatic cross-species comparison using a gene expression signature of MPNST-like mouse melanomas identified a subset of human melanomas with a similar histomorphology. Furthermore, this subset of human melanomas was found to be highly associated with a mast cell gene signature, and accordingly, mouse MPNST-like melanomas were also extensively infiltrated by mast cells and expressed mast cell chemoattractants similar to human counterparts. A transplantable mouse MPNST-like melanoma cell line recapitulated mast cell recruitment in syngeneic mice demonstrating that this cell state can directly reconstitute the histomorphological and microenvironmental features of primary MPNST-like melanomas. Our study emphasizes the importance of reciprocal, phenotype-dependent melanoma-immune cell interactions and highlights a critical role for mast cells in a subset of melanomas. Moreover, our BrafV600E-Cdk4R24C model represents an attractive system for the development of therapeutic approaches that can target the heterogeneous tumor microenvironment characteristic of human melanomas. Precis: Findings highlight the ability to study human melanoma heterogeneity in a mouse model, revealing how melanocyte-immune cell interactions contribute to the development of distinct subsets of melanomas within a single individual. on April 13, 2017. © 2015 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 28, 2015; DOI: 10.1158/0008-5472.CAN-15-1090