We recently found that mechanistic target of rapamycin complex 2 (mTORC2) is required for prostate cancer and leukemia driven by PTEN deletion validating mTORC2 as a therapeutic target (Guertin et al., Cancer Cell 2009; Kalaitzidas et al., Cell Stem Cell 2012); however, the exact function of mTORC2 in tumorigenesis remains a mystery. We also reported recently that mTORC2 is essential in brown adipose tissue for lipogenesis and in vitro for adipogenesis, a process requiring high glucose flux and de novo lipogenesis (Hung et al., Cell Reports 2014), suggesting mTORC2 may promote cancer by controlling glucose utilization and lipid biosynthesis. AKT and SGK are the best-understood mTORC2 substrates; however, we unexpectedly found that mTORC2 promotes lipogenesis independently of pan-AKT and SGK signaling revealing the existence of unidentified mTORC2 effectors, and thereby exposing major gaps in our understanding of mTORC2 and AKT function. The specific goal of this proposal is to elucidate the mechanisms by which mTORC2 controls cell metabolism through both AKT-dependent and AKT-independent pathways with the long-term goal of identifying metabolic requirements for cancer cell proliferation and survival, new targets for cancer drugs, and potential mechanisms of drug resistance. Through innovative approaches, outstanding collaborators, and our unique toolkit we tackle in this proposal some of the biggest unsolved mysteries and most controversial issues in the field. Our approach is multidisciplinary, taking advantage of state-of-the-art proteomic, genomic, metabolomic, and genome engineering strategies, and a diverse array of novel cell lines and in vivo mouse models all designed to overcome current roadblocks and technical hurdles to elucidating mTORC2's mechanisms of metabolic control. Because mTORC2 and AKT function at the interface of growth factor signaling and cell metabolism, our work will have broad implications for understanding and treating cancer, particularly those cancers driven by high PI3-kinase activity.
In the last decade scientists have come to appreciate that for cancer cells to proliferate and survive, they must reprogram their metabolism to fuel these processes. Thus, targeting the metabolic circuitry of cancer cells offers an important new avenue of therapeutic development. In this proposal, we develop innovative tools and utilize emerging technologies to address major gaps in our understanding of how the PI3-kinase/mTOR pathway, which functions at the interface of signal transduction and metabolism, promotes cancer with the long-term goal of identifying new drug targets and treatment strategies.
| Sanchez-Gurmaches, Joan; Tang, Yuefeng; Jespersen, Naja Zenius et al. (2018) Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis. Cell Metab 27:195-209.e6 |
| Secco, Blandine; Camiré, Étienne; Brière, Marc-Antoine et al. (2017) Amplification of Adipogenic Commitment by VSTM2A. Cell Rep 18:93-106 |
| Lee, Peter L; Jung, Su Myung; Guertin, David A (2017) The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond. Trends Endocrinol Metab 28:319-339 |
| Cederquist, Carly T; Lentucci, Claudia; Martinez-Calejman, Camila et al. (2017) Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue. Mol Metab 6:125-137 |
| Sanchez-Gurmaches, Joan; Hung, Chien-Min; Guertin, David A (2016) Emerging Complexities in Adipocyte Origins and Identity. Trends Cell Biol 26:313-326 |
| Lee, Peter L; Tang, Yuefeng; Li, Huawei et al. (2016) Raptor/mTORC1 loss in adipocytes causes progressive lipodystrophy and fatty liver disease. Mol Metab 5:422-32 |
| Tang, Yuefeng; Wallace, Martina; Sanchez-Gurmaches, Joan et al. (2016) Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism. Nat Commun 7:11365 |
