期刊
CELL REPORTS
卷 28, 期 9, 页码 2293-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.086
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资金
- Howard Hughes Medical Institute
- Cancer Prevention and Research Institute of Texas [RP170114, RP170633, RP180778]
- Once Upon a Time Foundation
- Ruth L. Kirschstein National Research Service Award Predoctoral Fellowships from the National Cancer Institute [F30 CA216885, F31 CA239330]
- Leopoldina Fellowship Program of the German National Academy of Sciences [LPDS2016-16]
We screen ion channels and transporters throughout the genome to identify those required by human melanoma cells but not by normal human melanocytes. We discover that Mucolipin-1 (MCOLN1), which encodes the lysosomal cation channel TRPML1, is preferentially required for the survival and proliferation of melanoma cells. Loss of MCOLNI/TRPML1 function impairs the growth of patient-derived melanomas in culture and in xenografts but does not affect the growth of human melanocytes. TRPML1 expression and macropinocytosis are elevated in melanoma cells relative to melanocytes. TRPML1 is required in melanoma cells to negatively regulate MAPK pathway and mTORC1 signaling. TRPML1-deficient melanoma cells exhibit decreased survival, proliferation, tumor growth, and macropinocytosis, as well as serine depletion and proteotoxic stress. All of these phenotypes are partially or completely rescued by mTORC1 inhibition. Melanoma cells thus increase TRPML1 expression relative to melanocytes to attenuate MAPK and mTORC1 signaling, to sustain macropinocytosis, and to avoid proteotoxic stress.
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