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

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 lineag...

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Veröffentlicht in:Molecular cell Jg. 77; H. 1; S. 120
Hauptverfasser: Vivas-García, Yurena, Falletta, Paola, Liebing, Jana, Louphrasitthiphol, Pakavarin, Feng, Yongmei, Chauhan, Jagat, Scott, David A, Glodde, Nicole, Chocarro-Calvo, Ana, Bonham, Sarah, Osterman, Andrei L, Fischer, Roman, Ronai, Ze'ev, García-Jiménez, Custodia, Hölzel, Michael, Goding, Colin R
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 02.01.2020
Schlagworte:
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
phenotype switching
melanoma
MITF
stearoyl CoA desaturase
metastatic dissemination
ATF4
fatty acid saturation
ISSN:1097-4164, 1097-4164
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Zusammenfassung: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 melanoma cell proliferation. By contrast MITF 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2019.10.014