Antagonistic roles for MITF and TFE3 in melanoma plasticity.

Melanoma cells can switch from a melanocytic and proliferative state to a mesenchymal and invasive state and back again. This plasticity drives intratumoral heterogeneity, progression, and therapeutic resistance. Microphthalmia-associated transcription factor (MITF) promotes the melanocytic/proliferative phenotype, but factors that drive the mesenchymal/invasive phenotype and the mechanisms that effect the switch between cell states are unclear. Here, we identify the MITF paralog, TFE3, and the non-canonical mTORC1 pathway as regulators of the mesenchymal state. We show that TFE3 expression drives the metastatic phenotype in melanoma cell lines and tumors. Deletion of TFE3 in MITF-low melanoma cell lines suppresses their ability to migrate and metastasize. Further, MITF suppresses the mesenchymal phenotype by directly or indirectly activating expression of FNIP1, FNIP2, and FLCN, which encode components of the non-canonical mTORC1 pathway, thereby promoting cytoplasmic retention and lysosome-mediated degradation of TFE3. These findings highlight a molecular pathway controlling melanoma plasticity and invasiveness.