1. Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity.
- Author
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Vivas-García Y, Falletta P, Liebing J, Louphrasitthiphol P, Feng Y, Chauhan J, Scott DA, Glodde N, Chocarro-Calvo A, Bonham S, Osterman AL, Fischer R, Ronai Z, García-Jiménez C, Hölzel M, and Goding CR
- Subjects
- Animals, Cell Differentiation physiology, Cell Line, Tumor, Cell Proliferation physiology, Down-Regulation physiology, Humans, Mice, Neoplasm Invasiveness pathology, Phenotype, Signal Transduction physiology, Adaptation, Physiological physiology, Fatty Acids metabolism, Melanoma metabolism, Microphthalmia-Associated Transcription Factor metabolism, Stearoyl-CoA Desaturase metabolism
- Abstract
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 MITF
High 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2020
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