Melanoma is a disease that demonstrates a wide range of clinical behavior from relatively indolent to aggressive metastatic disease. Since the identification of somatic mutations in the BRAF oncogene, targeted therapies directed toward mutated tumors have emerged and demonstrated dramatic clinical effect. Today, the combination of BRAF and MEK inhibitors are becoming the routine treatment of choice in metastatic melanoma. However, the downside of targeted therapies is development of resistance. In addition to targeted therapies a second generation of immune therapies has been developed with anti-PD1/PDL1 as the main choice of treatment. Previously, we have established that melanoma can be grouped in gene expression phenotypes with immune-rich melanomas having improved patient survival. We posit that using human tumor molecular and mutation data as a foundation for functional studies will lead us to novel insights about the fundamental biology of melanoma as well as provide us with inspiration for designing novel therapeutic strategies. Accordingly, our research program is focused on genomic tumor biology and the subsequent functional elucidation of biological mechanisms. We have observed that metastatic melanomas consist of two distinct lineages characterized by activated or inactivated melanocyte differentiation transcriptional programs. We are currently undertaking studies to understand the biology as well as defining novel therapeutic targets in the two lineage states of melanoma. Ultimately, our results will improve our understanding of the complexity of melanoma biology as well as having an impact in the clinical setting as such information can be used to develop prognostic and predictive molecular signatures.
In three consecutive papers we have firmly established the presence and significance of gene expression subtypes in melanoma. In metastatic melanoma the three subtypes; MITF-low Proliferative, MITF-high Pigmentation and High-immune response are the dominant ones suggesting two distinct lineages of melanoma (MITF-high and low), which is also supported by in vitro studies. In this project we will investigate the extent and mechanisms of lineage programming in melanoma. To do this, we will perform genome-wide siRNA screens on MITF-high and –low melanoma cells in combination with genomic analysis and suitable functional assays. We believe that increased biological understanding of the two main melanoma states will help us to identify novel therapeutic options.