Integrating systemic and molecular levels to infer key drivers sustaining metabolic adaptations

Metabolic adaptations to complex perturbations, like the response to pharmacological treatments in multifactorial diseases such as cancer, can be described through measurements of part of the fluxes and concentrations at the systemic level and individual transporter and enzyme activities at the molecular level. In the framework of Metabolic Control Analysis (MCA), ensembles of linear constraints can be built integrating these measurements at both systemic and molecular levels, which are expressed as relative differences or changes produced in the metabolic adaptation. Here, combining MCA with Linear Programming, an efficient computational strategy is developed to infer additional non-measured changes at the molecular level that are required to satisfy these constraints. An application of this strategy is illustrated by using a set of fluxes, concentrations, and differentially expressed genes that characterize the response to cyclin-dependent kinases 4 and 6 inhibition in colon cancer cells. Decreases and increases in transporter and enzyme individual activities required to reprogram the measured changes in fluxes and concentrations are compared with down-regulated and up-regulated metabolic genes to unveil those that are key molecular drivers of the metabolic response. Author summary Deciphering the essential events in the reprogramming of metabolic networks subjected to complex perturbations, including the response to pharmacological treatments in multifactorial diseases like cancer, is crucial for the design of efficient therapies. Yet, tools to infer the molecular drivers sustaining such metabolic responses remain elusive for large metabolic networks. Here we develop an efficient computational strategy that integrates measured changes at systemic and molecular levels and combines metabolic control analysis with linear programming tools to infer key molecular drivers sustaining the metabolic adaptations to complex perturbations, such as an antitumoral drug therapy. The collective behavior is approximated using linear expressions where the adaptation of systemic concentrations and fluxes to a perturbation is described as a function of the molecular reprogramming of transport and enzyme activities. Starting from measured changes in fluxes and concentrations, we identify changes in the reprogramming of transporter and enzyme activities that are required to orchestrate the metabolic adaptation of colon cancer cells to a cell cycle inhibitor.