Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated transcription factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, although how MITF promotes proliferation and suppresses invasion is poorly defined. Here, we show that MITF is a lineage-restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4-mediated feedback loop that maintains de-differentiation. Our results reveal that MITF is a lineage-specific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype switching, and highlight that cell phenotype dictates the response to drugs targeting lipid metabolism.
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ATF4, MITF, fatty acid saturation, melanoma, metastatic dissemination, phenotype switching, stearoyl CoA desaturase, Adaptation, Physiological, Animals, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Down-Regulation, Fatty Acids, Humans, Melanoma, Mice, Microphthalmia-Associated Transcription Factor, Neoplasm Invasiveness, Phenotype, Signal Transduction, Stearoyl-CoA Desaturase