When extracellular glucose and glutamine are abundant, cancer cells synthesize lipids, nucleic acids and non- essential amino acids from these precursors. However, when a cancer's growth exceeds its vascular supply, the cancer cells must adapt to a lower availability of these nutrients as well as oxygen. This past year, we discovered a novel mechanism by which some cancer cells adapt to metabolic stress. Although glutamine- dependent citrate production can support de novo lipid synthesis in hypoxic cells, metabolic tracing studies uncovered that up to 50% of lipids used for phospholipid biosynthesis in hypoxic cells came from exogenous sources. We were able to determine that hypoxia-induced macropinocytosis facilitates the uptake and incorporation of unsaturated phospholipids to maintain effective unsaturated fatty acid levels under conditions in which stearoyl CoA desaturase is inhibited by oxygen limitation. Follow-up studies have demonstrated that cellular scavenging of extracellular macromolecules is induced in an Ras-dependent fashion in transformed cells and provides a potent mechanism by which Ras-transformed cells can adapt to metabolic stress in their environment. Based on these recent discoveries, 3 Specific Aims are proposed for this competitive renewal: 1) Determine if the ability of Ras-induced lipid scavenging to support cell growth depends on the availability of extracellular unsaturated fatty acids. 2) Define the molecular basis by which Ras induces the uptake of unsaturated fatty acids. 3) Examine the role of autophagy components in Ras-mediated lipid uptake. Through these studies we hope to elucidate an important and novel mechanism by which cancer cells adapt to metabolic stress and determine whether this pathway can be therapeutically exploited.
How cancer cells maintain the synthesis and integrity of their phospholipid membranes when deprived of the fatty acid precursors, glucose and glutamine, is poorly understood. In this proposal, we propose experiments to determine the role of the oncogene Ras in directing the uptake of lipids from the extracellular environment and the ability of this process to overcome the need for glucose and/or glutamine to support phospholipid biosynthesis.
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