Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity

Mol Cell. 2020 Jan 2;77(1):120-137.e9. doi: 10.1016/j.molcel.2019.10.014. Epub 2019 Nov 13.

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 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.

Keywords: ATF4; MITF; fatty acid saturation; melanoma; metastatic dissemination; phenotype switching; stearoyl CoA desaturase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / physiology*
  • Animals
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Down-Regulation / physiology
  • Fatty Acids / metabolism*
  • Humans
  • Melanoma / metabolism*
  • Mice
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Neoplasm Invasiveness / pathology
  • Phenotype
  • Signal Transduction / physiology
  • Stearoyl-CoA Desaturase / metabolism*

Substances

  • Fatty Acids
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • Stearoyl-CoA Desaturase