TRPML1 Promotes Protein Homeostasis in Melanoma Cells by Negatively Regulating MAPK and mTORC1 Signaling

A major goal of studying melanoma is to identify therapeutic vulnerabilities that can be exploited to improve patient treatment. Melanoma cells are particularly sensitive to perturbations in ion homeostasis, especially when ion gradients are perturbed in combination with MAP kinase inhibition. I hypothesized that melanoma cells preferentially require certain ion channels and transporters for growth and survival. I thus screened ion channels and transporters throughout the genome to identify those required by human melanoma cells but not by normal human melanocytes. I discovered that Mucolipin-1 (MCOLN1), which encodes the lysosomal cation channel TRPML1, is preferentially required for the survival and proliferation of melanoma cells. Loss of MCOLN1/TRPML1 function impaired the growth of patient-derived melanomas in culture and in xenografts but did not affect the growth of human melanocytes. TRPML1 expression was elevated in melanoma cells relative to melanocytes and was required in melanoma cells to negatively regulate MAPK pathway and mTORC1 signaling. TRPML1-deficient melanoma cells exhibited decreased survival, proliferation, tumor growth, and macropinocytosis as well as serine depletion and proteotoxic stress. All of these phenotypes were partially or completely rescued by mTORC1 inhibition. Melanoma cells thus increase TRPML1 expression relative to melanocytes to attenuate MAPK and mTORC1 signaling. This helps melanoma cells prevent overactivation of these oncogenic signaling pathways, sustain macropinocytosis and avoid proteotoxic stress. Further investigation of the role of TRPML1 in melanoma may ultimately guide future patient therapies and contribute to our understanding of ion channels and transporters in cancer.