We compared gene expression signatures of aggressive amelanotic (Amela)
melanomas with those of slowly growing pigmented
melanomas (Mela), identifying pathways potentially responsible for the aggressive Amela phenotype. Both
tumors develop in mice upon conditional deletion in melanocytes of Ink4a/Arf tumor suppressor genes with concomitant expression of oncogene H-Ras(G12V) and a known
tumor antigen. We previously showed that only the aggressive Amela
tumors were highly infiltrated by leukocytes concomitant with local and systemic
inflammation. We report that Amela
tumors present a pattern of de-differentiation with reduced expression of genes involved in pigmentation. This correlates with reduced and enhanced expression, respectively, of
microphthalmia-associated (Mitf) and Pou3f2/Brn-2
transcription factors. The reduced expression of Mitf-controlled melanocyte
differentiation antigens also observed in some human cutaneous
melanoma has important implications for
immunotherapy protocols that generally target such
antigens. Induced Amela
tumors also express Epithelial-Mesenchymal-Transition (EMT)-like and TGFβ-pathway signatures. These are correlated with constitutive Smad3 signaling in Amela
tumors and
melanoma cell lines. Signatures of infiltrating leukocytes and some
chemokines such as
chemotactic cytokine ligand 2 (Ccl2) that contribute to leukocyte recruitment further characterize Amela
tumors. Inhibition of the
mitogen-activated protein kinase (MAPK) activation pathway in Amela
tumor lines leads to reduced expression of EMT hallmark genes and inhibits both proinflammatory
cytokine Ccl2 gene expression and Ccl2 production by the
melanoma cells. These results indicate a link between EMT-like processes and alterations of immune functions, both being controlled by the MAPK pathway. They further suggest that targeting the MAPK pathway within
tumor cells will impact
tumor-intrinsic oncogenic properties as well as the nature of the tumor microenvironment.