Over the last decade we have demonstrated that one of the essential functions of growth factor signaling is to direct the cell to take up and metabolie nutrients. As a corollary, many cancer cells survive in the absence of growth factor signaling because of oncogenic mutations that stimulate nutrient uptake. In the past, we have established that Akt activation promoted cell survival by stimulating glucose uptake and metabolism. As a result, Akt-transformed cells become addicted to glycolytic metabolism for the support of ATP production and for the production of anabolic precursors. In addition, we discovered that Myc activation directs the uptake and metabolism of glutamine, which represents a second major metabolic substrate required for cell proliferation. When extracellular glucose and glutamine are abundant, cancer cells primarily synthesize lipids, nucleic acids, and non-essential amino acids from these precursors. Most cancer cells when deprived of glucose and/or glutamine undergo cell cycle arrest or apoptosis. Only a few cancer types, exemplified by pancreatic cancers, can continue to grow when their extracellular environment becomes depleted of these key metabolic substrates. Virtually every pancreatic cancer harbors a Ras mutation. Recently Ras-transformed pancreatic cancer cells were discovered to be able to proliferate in media depleted of either glutamine or essential amino acids. Ras-induced macropinocytosis allows pancreatic cancer cells to utilize extracellular proteins as a source of amino acids for continued protein synthesis. In studying this pathway, we have discovered that activated mTORC1 is a potent suppressor of the cellular utilization of extracellular proteins as a source of amino acids. In this proposal, we seek to further explore this paradoxical finding.
Three Specific Aims are proposed: 1) Define the role of mTORC1 in the regulation of Ras-dependent protein uptake and degradation. 2) Determine the upstream regulators and downstream effectors of mTORC1-mediated suppression of extracellular protein uptake and degradation. 3) Determine if pharmacologic inhibition of mTOR can be combined with treatments that impair/exploit Ras-induced macropinocytosis in the therapy of genetically engineered mouse models of Ras-induced pancreatic ductal adenocarcinoma (PDAC) and human PDAC xenografts. Through these studies, we hope to elucidate a novel and underappreciated mechanism by which Ras-transformed cells adapt to metabolic stress and determine whether this pathway can be therapeutically exploited.

Public Health Relevance

How cancer cells acquire a sufficient balance of amino acids necessary to engage in net protein synthesis remains poorly understood. Recently, cancers carrying Ras mutations were shown to engage in the uptake and degradation of extracellular proteins to maintain their anabolic supply of amino acids. How this use of extracellular proteins is regulated by nutrient sensing pathways such as those involving mTORC1 and GCN2 will be examined with the goal of therapeutically exploiting this knowledge to enhance pancreatic cancer treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular Oncogenesis Study Section (MONC)
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Spalholz, Barbara A
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Sloan-Kettering Institute for Cancer Research
New York
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Gao, Minghui; Yi, Junmei; Zhu, Jiajun et al. (2018) Role of Mitochondria in Ferroptosis. Mol Cell :
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