A Preclinical Model of Malignant Peripheral Nerve Sheath Tumor-like Melanoma Is Characterized by Infiltrating Mast Cells

Abstract

Human melanomas exhibit considerable genetic, pathologic, 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 immune cell-rich amelanotic melanomas developed simultaneously in Cdk4R24C-mutant mice upon melanocyte-specific conditional activation of oncogenic BrafV600E and a single application of the carcinogen 7,12-dimethylbenz(a)anthracene. Interestingly, amelanotic melanomas showed morphologic 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 histomorphologic 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. Cancer Res; 76(2); 251-63. Ó2015 AACR.

Are Mast Cells MASTers in Cancer?

“…There are certain tumors such as breast cancer (106, 107, 109) in which mast cells always appear to play an antitumorigenic role. The role of mast cells in the pathogenesis of human melanomas is still unclear and appears to depend on both the microlocalization of these cells (43) and the subtypes of tumor (83). …”

“…There is increasing evidence that different stages of tumors can be associated with qualitative and quantitative changes in different types of immune cells in the periphery and center of tumors (146, 147). The pro- or antitumorigenic role of mast cells in different types of melanomas remains controversial (83, 148). Siiskonen and collaborators found that tryptase + chymase + mast cells in perilesional stroma of melanoma play a protective role (43).…”

“…Within the last years, gene expression profiling has demonstrated that several individual human cancers (e.g., melanoma, gastric, lung, and breast cancers) are heterogeneous with a spectrum of molecular changes (83, 175–178). The complex heterogeneity (spatial, temporal, intratumor, intertumor) of the tumor microenvironment adds an additional layer of complexity (179, 180).…”

Human mast cells and basophils—How are they similar how are they different?

“…By contrast, in breast cancer mast cells appear to play an anti‐tumorigenic role. The role of mast cells in the pathogenesis of human melanomas is still unclear and depends on both the microlocalization of these cells and the subtypes of tumor . These results suggest that the contribution of mast cells to cancer is tumor dependent.…”

The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung

“…In the case of melanoma, there is substantial documentation from both clinical studies and from animal models supporting that MCs participate in this pathology [14–22] (reviewed in [12]). However, there is still only little knowledge of the mechanism(s) by which MCs contribute to this malignancy.…”