Ensemble modeling of cancer metabolism

The metabolic behavior of cancer cells is adapted to meet their proliferative needs, with notable changes such as enhanced lactate secretion and glucose uptake rates. In this work, we use the Ensemble Modeling (EM) framework to gain insight and predict potential drug targets for tumor cells. EM generates a set of models which span the space of kinetic parameters that are constrained by thermodynamics. Perturbation data based on known targets are used to screen the entire ensemble of models to obtain a sub-set, which is increasingly predictive. EM allows for incorporation of regulatory information and captures the behavior of enzymatic reactions at the molecular level by representing reactions in the elementary reaction form. In this study, a metabolic network consisting of 58 reactions is considered and accounts for glycolysis, the pentose phosphate pathway, lipid metabolism, amino acid metabolism, and includes allosteric regulation of key enzymes. Experimentally measured intracellular and extracellular metabolite concentrations are used for developing the ensemble of models along with information on established drug targets. The resulting models predicted transaldolase (TALA) and succinyl-CoA ligase (SUCOAS1m) to cause a significant reduction in growth rate when repressed, relative to currently known drug targets. Furthermore, the results suggest that the synergistic repression of transaldolase and glycine hydroxymethyltransferase (GHMT2r) will lead to a threefold decrease in growth rate compared to the repression of single enzyme targets.