Transcriptional Reprogramming in Melanoma Plasticity

Project Summary/Abstract This application focuses on advanced melanoma, a highly aggressive type of skin cancer that arises from the pigment-producing melanocytes of the body. Despite recent advances in molecularly targeted therapy and immunotherapeutic agents with impressive response rates, there remain patients who either do not respond to

such therapies or who eventually relapse. The 5-year overall survival rate for metastatic melanoma is below 20%. Progressive dedifferentiation and phenotypic switching of melanoma cells under cellular stress are considered to be a major driver for both tumor progression and therapy resistance. However, the molecular

mechanisms that govern this process, and their interplay with genetic lesions and the tumor microenvironment are poorly understood. TFEB is a member of the MiT/TFE family of transcription factors and master regulators of cell differentiation pathways. Our preliminary studies identified TFEB repression as a novel dependency of

oncogene-driven melanoma progression. We showed that TFEB activation globally re-invigorates transcriptional differentiation of melanocytes, while its inactivation provokes phenotypic transition towards the invasive and drug-resistant states that is associated with aberrant TGF-b upregulation. Furthermore,

transcriptomic and immune cell profiling of tumors from primary melanoma patients confirmed dampened TFEB expression and function that also correlates with tumors’ immune evasive microenvironment. These findings lead us to hypothesize that TFEB-mediated transcriptional reprogramming of melanoma cell

differentiation states represents a key mechanism disabling melanoma progression, which also reshapes tumor immune microenvironment for enhanced anti-tumor immunity. We will test the hypothesis by (Aim 1) defining the molecular mechanisms of TFEB-mediated transcriptional reprogramming of melanoma cell plasticity and phenotype switching; and by (Aim 2) investigating in detail the in vivo impact of

TFEB alteration in melanoma progression and immune evasion. Successful completion of this study will provide mechanistic insights into tumor cell-switching processes and hold promise for the development of novel therapeutic strategies to reverse this process for the prevention and elimination of tumor metastasis and

recurrence.