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We sought to assess cancer cell viability in the context of glycolytic versus oxidative phosphorylation carbon source availability from cell lines and expression data from variably glycolytic human tumors. We performed an RNAi screen of genes consisting of the cytosolic machinery for ATP production and regulation of bioenergetic output in cancer cells in glycolytic or oxidative phosphorylation (OXPHOS) conditions. We identified the pentose phosphate pathway as requisite for viability under glycolytic conditions and mTOR signaling as requisite for viability under OXPHOS conditions. We then characterized gene sets within this panel to identify similarities and differences amongst RNA-seq profiles across variably glycolytic cancer types. This analysis identified glycolytic tumor profiles from non-glycolytic tumor profiles. Our analyses support classification of tumors by metabolic phenotype.

Cancer cells utilize variable metabolic programs in order to maintain homeostasis in response to environmental challenges. To interrogate cancer cell reliance on glycolytic programs under different nutrient availabilities, we analyzed a gene panel containing all glycolytic genes as well as pathways associated with glycolysis. Using this gene panel, we analyzed the impact of an siRNA library on cellular viability in cells containing only glucose or only pyruvate as the major bioenergetic nutrient source. From these panels, we aimed to identify genes that elicited conserved and glycolysis-dependent changes in cellular bioenergetics across glycolysis-promoting and OXPHOS-promoting conditions. To further …