mTORC2 Promotes Tumorigenesis via Lipid Synthesis

Publication date: 11 December 2017
Source:Cancer Cell, Volume 32, Issue 6
Author(s): Yakir Guri, Marco Colombi, Eva Dazert, Sravanth K. Hindupur, Jason Roszik, Suzette Moes, Paul Jenoe, Markus H. Heim, Isabelle Riezman, Howard Riezman, Michael N. Hall
Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production.

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Teaser

Guri et al. find that mTORC2 promotes de novo fatty acid and lipid synthesis. This pathway is elevated in human liver cancer and drives hepatosteatosis and liver cancer in mice, whereas its inhibition or deletion of Rictor reduces mouse tumors, suggesting this pathway as a therapeutic target in liver cancer.


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