Characterizing the Roles of BRAF, PTEN and Cdkn2a in Novel Mouse Models of Melanoma Formation and Progression

There will be an estimated 60,000 new cases and nearly 8000 deaths in the US this year due to malignant melanoma. People living in the US are expected to have a 1 in 71 lifetime risk of developing the disease. Activating mutations in BRAF occur in approximately 60% of melanomas and in 80% of benign melanocytic nevi. PTEN is a tumor suppressor that has been shown to be deleted or epigenetically silenced in approximately 30% of melanomas. Cdkn2a is a locus encoding 2 tumor suppressors in alternate reading frames that has been found to be mutated in up to 40% of familial melanomas and is near universally lost in human melanoma cell lines. We used these data to generate novel mouse models of metastatic melanoma involving an inducible Cre transgenic mouse (Tyr::CreER-T2). We demonstrate that Pten loss, Cdkn2a loss or Braf activation in isolation does not induce melanoma. In contrast, when Braf activation is combined with Pten loss, mice develop aggressive pigmented melanomas with 100% penetrance and a mean tumor free survival of 19.5 days. Melanocytic proliferation occurs immediately following induction with virtually no latency. Expansile metastases are observed in lymph nodes and isolated tumor cells are present in the lungs and brain. Both incipient and established melanomas are sensitive to the mTOR inhibitor rapamycin. Furthermore, mTORC1 signaling is prevented upon rapamycin treatment, but mTORC2, MAPK, and Akt signaling appear to be unaffected. Additionally, when Cdkn2a loss is combined with Braf activation, the mice develop a nevic phenotype with complete penetrance and stochastic progression to melanoma. Median melanoma free survival is 85.5 days and tumors are metastatic to lymph nodes in 100% of mice. These novel mouse models of melanoma will likely be useful in the study of the biology of metastasis, in tumor immunology, and in new models of preclinical testing