期刊
MOLECULAR CELL
卷 77, 期 1, 页码 120-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2019.10.014
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资金
- Ludwig Institute for Cancer Research, USA
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, UK
- National Institutes for Health (NIH) [PO1 CA128814-06A1]
- NIH Cancer Center, USA [P30 CA030199]
- European Union [FP7-PEOPLE: PIEF-GA-2013-626098]
- EMBO Long-Term Fellowship [ALTF 800-2013]
- Comunidad de Madrid, Spain
- Spanish government grant Mineco/FEDER, Spain [SAF2016-79837-R]
- Universidad Rey Juan Carlos-Banco de Santander, Spain, (grupo excelencia QUINANOAP)
- Kennedy Trust, UK
- DFG Excellence Cluster ImmunoSensation2, Germany [EXC2151]
- Ayudas Atraccion de Talento [2017-T1/BMD-5334]
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 lineagespecific 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.
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