Vivas-García, YurenaFalletta, PLiebing, JLouphrasitthiphol, PFeng, YChauhan, JScott, DAGlodde, NChocarro-Calvo, ABonham, SOsterman, AFischer, RRonai, ZGarcía-Jiménez, CHölzel, MGoding, CR2024-01-262024-01-262020-01-02Mol Cell . 2020 Jan 2;77(1):120-137.e91097-2765https://hdl.handle.net/10115/29028Phenotypic 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.engATF4MITFfatty acid saturationmelanomametastatic disseminationphenotype switchingstearoyl CoA desaturaseinfo:eu-repo/semantics/article10.1016/j.molcel.2019.10.014info:eu-repo/semantics/restrictedAccess