Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.molcel.2019.10.014

Type

Journal article

Journal

Mol Cell

Publication Date

02/01/2020

Volume

77

Pages

120 - 137.e9

Keywords

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