Decoding and targeting the PI3K-mTOR signaling network in cancer The major growth factor signaling pathways in normal cells (e.g., PI3K and RAS) are also the ones that are most frequently genetically activated in cancer cells, leading to cell autonomous growth and proliferation. mTOR complex 1 (mTORC1) is a major driver of cell growth and is aberrantly activated in the majority of human cancers. This activation occurs through a network of upstream oncogenes and tumor suppressors that converge on a small G protein switch directly upstream of mTORC1. This switch involves the tuberous sclerosis complex (TSC) tumor suppressors, which form a protein complex (the TSC complex) that regulates a member of the Ras family of GTPases, called Rheb, an essential direct activator of mTORC1. Our previous studies have found that the TSC complex and Rheb serve as the key molecular link between the PI3K pathway and mTORC1 signaling. Over the past decade, our laboratory has been at the forefront of major discoveries regarding the PI3K-mTOR signaling network and its role in both normal cellular physiology and the aberrant growth of tumor cells. This grant is focused on defining the complex wiring of the oncogenic signaling network upstream of the TSC complex and mTORC1 and the downstream consequences stemming from the common dysregulation of this network in human cancers. The research plan builds on our breakthrough findings from the past 5 years in two major areas: 1) Upstream signaling - To define the molecular regulation of the TSC- Rheb-mTORC1 circuit as a shared target of multiple oncogenic signaling pathways and its role in the development of resistance to targeted therapeutics acting on these upstream pathways; 2) Downstream consequences - To delineate the critical metabolic and adaptive response processes controlled by the PI3K- mTOR pathway that underlie the uncontrolled growth and survival of cancer cells and therapeutic opportunities arising from manipulation of these processes. These collective studies emphasize the need to gain a deep understanding of the molecular wiring of this ubiquitous signaling network and how it interfaces with key cellular processes in order to reveal novel vulnerabilities that can be exploited to selectively kill cancer cells, the majority of which exhibit perturbations in the contol of this network.
Research under this grant is aimed at defining how the major lines of communication function in normal cells and become dysfunctional in cancer cells to promote uncontrolled cell growth, with a focus on one of the most commonly activated pathways in human cancers (the mTOR pathway). Development of novel therapeutic strategies to destroy cancer cells displaying activation of this pathway is a major aim of these studies.
|Longchamp, Alban; Mirabella, Teodelinda; Arduini, Alessandro et al. (2018) Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production. Cell 173:117-129.e14|
|Hoxhaj, Gerta; Hughes-Hallett, James; Timson, Rebecca C et al. (2017) The mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels. Cell Rep 21:1331-1346|
|Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Martín-Martín, Natalia et al. (2017) mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547:109-113|
|Kelsey, Ilana; Zbinden, Marie; Byles, Vanessa et al. (2017) mTORC1 suppresses PIM3 expression via miR-33 encoded by the SREBP loci. Sci Rep 7:16112|
|Valvezan, Alexander J; Turner, Marc; Belaid, Amine et al. (2017) mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability. Cancer Cell 32:624-638.e5|
|Ben-Sahra, Issam; Manning, Brendan D (2017) mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol 45:72-82|
|Shimizu, Kouhei; Fukushima, Hidefumi; Ogura, Kohei et al. (2017) The SCF?-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis. Sci Signal 10:|
|Manning, Brendan D; Toker, Alex (2017) AKT/PKB Signaling: Navigating the Network. Cell 169:381-405|
|Breitkopf, Susanne B; Ricoult, Stéphane J H; Yuan, Min et al. (2017) A relative quantitative positive/negative ion switching method for untargeted lipidomics via high resolution LC-MS/MS from any biological source. Metabolomics 13:|
|Howell, Jessica J; Hellberg, Kristina; Turner, Marc et al. (2017) Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex. Cell Metab 25:463-471|
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