Ras‐Induced Macropinocytosis: Metabolic adaptation to signaling in the absence of adequate nutrients

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. In the past year, we have seen a major 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 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. This pathway of cellular acquisition of bioenergetic substrates has previously escaped detection because, in complete medium, the utilization of macropinocytosed proteins as metabolic substrates is actively suppressed. The molecular details of this suppression and the implication of these studies to understanding both cancer and wound repair will be discussed.