Lipid dependence in Ras-driven tumors

Over past decade, metabolic alterations in cancer cells have received a substantial amount of interest. It had been established that cancer cells undergo a significant amount of metabolic alterations, and some of these alterations are similar to those in normal highly proliferative cells. However, it is becoming more apparent that many of the metabolic alterations are specific to particular oncogenic signaling pathways. Although altered metabolic machinery makes cancer cells more efficient at promoting growth when nutrients are supplied at the sufficient amounts, the dependency of cancer cells on particular metabolic reprogramming deems cancer cells susceptible to disruptions within metabolic network. Thus, the identification of metabolic weaknesses of cancer cells create a platform for therapeutic interventions. The conversion of normal cells to cancer cells involves a shift from catabolic to anabolic metabolism involving increased glucose uptake and the diversion of glycolytic intermediates into nucleotides, amino acids and lipids needed for cell growth. An underappreciated aspect of nutrient uptake is the utilization of serum lipids. We investigated the dependence of human cancer cells on serum lipids and report here that Ras-driven human cancer cells are uniquely dependent on serum lipids for both proliferation and survival. Moreover, Ras-driven cancer cells fail to adapt lipid metabolism upon lipid deprivation. Removal of serum lipids also sensitizes Ras-driven cancer cells to rapamycin. Suppressing pinocytosis in Ras-driven cancer cells similarly created sensitivity to suppression of mTORC1 - the mammalian/mechanistic target of rapamycin. The findings reported here reveal an enhanced need for serum lipids in Ras-driven human cancer cells that creates a synthetic lethal phenotype for suppressing mTORC1. While depriving humans of serum lipids is not practical, suppressing uptake of lipids is possible and could be exploited therapeutically, presenting speculated that this property displayed by Ras-driven cancer cells represents an Achilles\u27 heel for the large number of human cancers that are driven by activating Ras mutations. mTOR has long been known to respond to amino acids, glucose and energy. However, lipids are another essential nutrient, and sensing mechanism on sufficiency of lipid precursors is not yet known. Based on the central position of PA in lipid biosynthesis, and its involvement in mTOR regulation, here we show that PA feeds into mTOR as a metabolite for sensing lipid precursors. In Ras-driven cells, PLD activity increase due to lipid withdrawal may be a mechanism to keep mTOR active during metabolic insufficiency stress