Cellular growth conditions are sensed not only by metabolic pathways in the form of available carbon and nitrogen sources but also by signaling networks that tightly coordinate the consumption of these metabolic substrates with the control of other cellular processes. It is this coincident regulation of metabolism and other aspects of cell physiology (e.g., organelle biogenesis, cell-cycle entry, etc.) that allows anabolic cell growh and proliferation to proceed. However, the same signaling networks that perceive normal growth signals to coordinately regulate growth processes, including metabolism, are also those most commonly corrupted in human cancers, such as the PI3K and Ras pathways. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell growth and a shared downstream effector of these pathways. How mTORC1 influences the downstream cellular processes underlying cell growth is not fully understood. Recent published and unpublished data from our lab indicate that mTORC1, in addition to its established role in promoting protein synthesis, stimulates de novo synthesis of the two other major building blocks of the cell, lipids and nucleotides. Therefore, in response to growth signals, mTORC1 promotes cell growth, at least in part, by inducing key anabolic processes. Due to a large number of upstream oncogenes and tumor suppressors, mTORC1 is constitutively activated in over 50% of human cancers, across nearly all lineages. While it is now well recognized that altered cellular metabolism is a ubiquitous feature of cancer, how oncogenic pathways promote the metabolic changes that drive cell autonomous growth is largely unknown. Here, we hypothesize that mTORC1, through its downstream control of protein, lipid, and nucleotide synthesis, is a key conduit between common oncogenic signaling events and the anabolic reprogramming of cancer cells. This proposal extends our previous mechanistic studies on mTORC1 inducing lipid synthesis through the SREBP family of transcription factors (Aim 1) and de novo pyrimidine synthesis through the S6K1-mediated phosphorylation of CAD, the rate-limiting enzyme in this pathway (Aim 2). The effects of oncogenic PI3K and Ras signaling on lipid and nucleotide synthesis downstream of mTORC1 will be determined. We will also establish the role of these mTORC1-stimulated changes in cellular metabolism in promoting cell growth and tumorigenesis. Under Aim 3, we will combine specific genetic and pharmacological perturbations with unbiased metabolomics to characterize novel mTORC1- or mTORC2-dependent points of metabolic regulation within the PI3K signaling network. In all of these studies, we will employ both cell-based systems and mouse tumor models, with an emphasis on defining molecular mechanisms of metabolic control in cancer cells and the identification of therapeutic opportunities in the form of targeting key metabolic enzymes and vulnerabilities to selectively kill cancer cells.
NIH ExPorter
NIH ExPorter