Abstract PL02-03: Ras-induced macropinocytosis: Metabolic adaptation to signaling in the absence of adequate nutrients.

Abstract

Abstract Under conditions of an abundant supply of extracellular glucose and glutamine, cancer cells synthesize lipids, nucleic acids, and non-essential amino acids from these precursors. However, when cancer grows to exceed its vascular supply, cells must adapt to lower availability of essential nutrients and oxygen. This past year we have seen a significant breakthrough in the discovery of novel mechanisms by which cancer cells adapt to metabolic stress. It was previously determined that glutamine-dependent lipid synthesis could support de novo lipid synthesis under hypoxia but metabolic tracing studies uncovered that over 50% of lipids used in phospholipid biosynthesis in hypoxic cells come from exogenous sources. We were able to determine that hypoxia-induced macropinocytosis facilitates the uptake and incorporation of unsaturated phospholipids to maintain effective unsaturated lipid levels under conditions in which stearoyl-CoA desaturase is inhibited by oxygen limitation. Follow up studies, in collaboration with others, have demonstrated that this property of cellular scavenging of extracellular macromolecules is induced in a Ras-dependent fashion in transformed cells and provides a potent mechanism by which Ras-transformed cells can adapt to metabolic stress in their environment. How these insights can be used to develop novel therapeutic strategies to address Ras-induced tumors will be discussed. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL02-03. Citation Format: Craig B. Thompson. Ras-induced macropinocytosis: Metabolic adaptation to signaling in the absence of adequate nutrients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL02-03.