Mechano-metabolism of adherent cells in 2D and 3D microenvironments

Cells regulate their metabolic activity in response to the mechanical and chemical properties of their microenvironment. To elucidate how a cell’s morphology, contractility and its energetic demands are controlled by the microenvironment, we developed a non-equilibrium, active chemo-mechanical model that makes quantitative predictions of ATP consumption associated with stress fiber assembly as a function of extracellular matrix mechanical properties. We study the metabolic budget of MDA-MB-231 breast cancer cells cultured in different density 3D collagen gels and on different stiffness 2D polyacrylamide substrates and predict unique trends in cell shape consistent with experimental observations. We show that the cell contractility monotonically increases with stiffness as does the steady state level of ATP consumption. By accounting for the mechano-sensitive activation of AMPK, we show that our model could also predict ATP replenishment, and we find with experimental measurements increasing levels of activated AMPK as a function of matrix stiffness. The insights gained from the predictive model on how the cell tailors its metabolic budget in response to the microenvironment can be used to understand mechanosensitive regulation of metabolic processes and of physiological events such as metastasis and tumor progression during which cells experience dynamic changes in their microenvironment and metabolic state.