Melanoma is the most deadly form of skin cancer that kills over 20,000 Europeans each year and incidence continues to rise rapidly. BRAFV600E inhibitors have led to clinically significant improvements in outcomes for melanoma patients, yet many patients with metastatic melanoma rapidly succumb to the disease due to eventual chemoresistance, or insensitivity to the drug. Thus, it is critical to identify new therapies that can act alone, or be combined with available treatments for enhanced efficacy and/or to overcome drug resistance.
Evidence from human melanoma indicates that the melanocyte lineage is critical for melanoma survival and contributes to therapeutic resistance. MITF is a highly conserved “master melanocyte regulator” with a complex role in melanoma. Our lab has developed two temperature sensitive zebrafish melanoma models (earlier published BRAFV600E mitf and a new BRAF-independent model p53 mitf), both carrying the mitfv7 splice site mutation that enables us to conditionally control its endogenous activity by adjusting the water temperature. We showed that the MITF activity is crucial for melanocyte survival and that both mutated BRAF and p53 deficiency are oncogenic with low levels of MITF, and result in fish nevi and melanoma resembling the pathology of human disease. Complete inhibition of MITF activity leads to rapid tumor regression, but once its activity is restored the melanomas recur at the same site as the original tumor. This suggests that a subpopulation of cancer initiating cells remains following melanoma regression and is capable of repopulating the tumor. We have been able to show that some cells remaining at the sites of regression express BRAFV600E and we are currently searching for other markers. Our goal is to identify the molecular signatures of these proposed melanoma stem cells and to develop approaches to visualize and target these subpopulations. We are using histopathology studies, molecular and lineage tracing imaging methods and melanocyte lineage transgenes in our genetic zebrafish models, as well as zebrafish melanoma cell culture to study the nature of the cell of origin for the tumor recurrence.