Computational modeling of cancer cell metabolism along the catabolic-anabolic axes

Abstract

Abnormal metabolism is a hallmark of cancer. Initially recognized through the observation of aerobic glycolysis in cancer nearly a century ago. Also, we now know that mitochondrial respiration is also used by cancer for progression and metastasis. However, it remains largely unclear the mechanisms by which 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. Here, we formulate a phenotypic model for cancer metabolism by coupling master gene regulators (AMPK, HIF-1, Myc) with key metabolic substrates (glucose, fatty acid, and glutamine). The model predicts that cancer cells can acquire 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. Using this framework, we quantified gene and metabolic pathway activity respectively by developing scoring metrics based on gene expression. We validated the model-predicted gene-metabolic pathway association and the characterization of the four metabolic phenotypes by analyzing RNA-seq data of tumor samples from TCGA. Strikingly, carcinoma samples exhibiting hybrid metabolic phenotypes are often associated with the worst survival outcomes relative to other metabolic phenotypes. Our mathematical model and scoring metrics serve as a platform to quantify cancer metabolism and study how cancer cells adapt their metabolism upon perturbations, which ultimately could facilitate an effective treatment targeting cancer metabolic plasticity. Statement of significanceWe present 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. Our work characterizes four main metabolic phenotypes in cancer - OXPHOS, glycolysis, hybrid, glutamine-dominant and demonstrates the critical role of Myc on glutamine metabolism in all four phenotypes. The characterization of metabolism can guide our evaluation of patient survival across cancer types.