Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

Journal article

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.

Authors: Vivas-García, Y; Falletta, P; Liebing, J; Louphrasitthiphol, P; Feng, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Molecular Cell
• Volume: 77
• Issue: 1
• Pages: 120-137
• Publication date: 2019-11-13
• Acceptance date: 2019-10-10
• DOI: 10.1016/j.molcel.2019.10.014
• ISSN: 1097-2765
• Language: English
• Keywords: ATF4; phenotype-switching; melanoma; stearoyl CoA desaturase; fatty acid saturation; MITF; FFR