Abstract IA02: The PI3K-mTOR signaling network and tumor cell metabolism

Abstract

Abstract The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a key signaling node, universal to eukaryotic cells, which links the sensing of nutrients to the coordinated regulation of nutrient metabolism. mTORC1 has the ability to integrate signals from a variety of sources, including intracellular nutrients and secreted growth factors. The activation state of mTORC1 is tightly controlled through a small G protein switch involving the TSC1-TSC2-TBC1D7 complex (the TSC complex) and the Ras-related small G protein Rheb. The direct phosphorylation and inhibition of the TSC complex by the protein kinase Akt provides the major mechanistic link between growth factor signaling and mTORC1. Current evidence indicates that this signal is integrated with amino acid sensing pathways upstream of mTORC1 through independent spatial control over the subcellular localization of the TSC complex and mTORC1 to the surface of the lysosome. This talk will include unpublished data on additional signals that regulate mTORC1 through the TSC-Rheb circuit. Our data suggest that both physiologic growth signals and common oncogenic events in cancer activate mTORC1 through mechanisms leading to dissociation of the TSC protein complex from the lysosomal subpopulation of Rheb, which is required for mTORC1 activation. Physiologic and pathologic activation of PI3K-mTOR signaling results in a shift from catabolic processes to anabolic biosynthetic processes. This pathway acutely responds to feeding and is also frequently and aberrantly activated in human cancers. Through unbiased genomic and metabolomic approaches, we have found that, in addition to its established roles in promoting protein synthesis and inhibiting autophagy, mTORC1 stimulates changes in specific metabolic pathways through transcriptional and post-translational effects on metabolic enzymes. In this manner, mTORC1 serves to link growth signals to metabolic processes that promote the growth of cells, tissues, and tumors, including the de novo synthesis of proteins, lipids, and nucleotides. Research in our lab is focused on understanding the coordinated anabolic program downstream of PI3K-mTOR signaling and identifying metabolic vulnerabilities stemming from uncontrolled pathway activation that can be targeted in tumors. I will discuss our latest data on additional metabolic enzymes under control of the PI3K-mTOR network that contribute to an integrated metabolic program underlying cell growth in both normal and cancer cells. Citation Format: Brendan D. Manning. The PI3K-mTOR signaling network and tumor cell metabolism [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA02.