mTORC2-Driven Lipid Synthesis Promotes Liver Tumorigenesis

The distinct protein complexes mTORC1 and mTORC2 are components of the mTOR signaling node, which is frequently dysregulated in cancer and regulates metabolism-associated pathways to drive cell growth. Although protumorigenic mechanisms underlying the role of mTORC1 in metabolism have been described, less is known about the role of mTORC2 in tumor metabolism and cancer. Guri and colleagues generated mice (termed L-dKO) that exhibited liver-specific depletion of Pten, which negatively regulates mTORC1 and mTORC2, and Tsc1, which controls the activation of mTOR. L-dKO mice exhibited increased mTOR signaling, liver growth, and the presentation of hepatocellular carcinoma (HCC), liver cancer, and occasionally cholangiocarcinoma. Longitudinal integrated proteomic and phosphoproteomic analyses revealed that fatty acid (FA) and lipid synthesis pathways were upregulated in L-dKO mice compared with control littermates. Further, L-dKO mice exhibited FA accumulation, which is associated with hepatosteatosis; pharmacologic or targeted genetic ablation of FA synthase reduced FA accumulation, liver tumor burden, and liver damage markers, but did not inhibit mTOR signaling, in L-dKO mice. Transcriptomic and immunoblotting analyses revealed that L-dKO livers exhibited increases in enzymes that mediate de novo biosynthesis of sphingolipids such as serine palmitoyltransferase (SPT), and sphingolipids, particularly glucosylceramide. Treatment with an SPT inhibitor or targeted knockdown of the glucosylceramide synthesis enzyme reduced tumor growth in L-dKO mice. Similarly, L-dKO livers exhibited increases in the glycopeptiolipid cardiolipin, which supports oxidative phosphorylation, and mitochondrial function. Treatment with an mTORC1/2 inhibitor or targeted knockdown of Rictor (termed L-triKO) resulted in reduced mTORC2 signaling, FA levels, FA and lipid synthesis enzymes, and tumorigenicity. Consistent with these findings, FA and lipid biosynthetic enzymes were elevated in HCCs from steatotic patients and in livers from non-cancer steatotic patients. These results show that mTORC2-induced FA and lipid biosynthesis promotes steatotic HCC tumorigenesis and suggest a chemoprevention strategy for patients with hepatosteatosis.

Guri Y, Colombi M, Dazert E, Hindupur SK, Roszik J, Moes S, et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell 2017;32:807–23.

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