Elucidating Cancer Metabolic Flexibility: When Genetic and Metabolic States Converge

Abnormal metabolism is a hallmark of cancer characterized by the observation of aerobic glycolysis in cancer. Recently, we observed that mitochondrial respiration is also used by cancer for progression and metastasis. However, little is known on how cancer cells mix and match different metabolic modalities (oxidative/reductive) and leverage various metabolic ingredients (glucose, fatty acids, glutamine) to meet their bioenergetic and biosynthetic needs. A theoretical framework that integrates both catabolic and anabolic modes of cancer metabolism, considering the complex interplay between glucose, fatty acids, and glutamine, by coupling genetic regulation with metabolic pathways will be discussed. The model predicts that cancer cells can acquire mainly four metabolic phenotypes: a catabolic phenotype characterized by vigorous oxidative processes - O, an anabolic phenotype characterized by pronounced reductive activities - W, and two complementary hybrid metabolic states - one exhibiting both high catabolic and high anabolic activity - W/O, and the other relying mainly on glutamine oxidation - Q. Our model demonstrates the critical role of Myc on glutamine metabolism in all four metabolic phenotypes. Using this framework, we quantify gene and metabolic pathway activity respectively by developing scoring metrics based on gene expression. This mathematical model and scoring metrics serve as a platform to quantify cancer metabolism and study how cancer cells adapt their metabolism upon perturbations.