Computational modeling of mechano-metabolic adaptation to a stiff microenvironment in Cancer cells

Extracellular matrix (ECM) is a highly dynamic cohort of macromolecules present in the cellular microenvironment that regulates cellular behavior chemically and mechanically. Numerous studies have demonstrated the effect of mechanical cues on cellular differentiation and morphology. These studies also highlight the imperative role of ECM in the activation of specific signaling pathways through which ECM influences cellular behavior. Continuous remodeling of the Tumor microenvironment, which also includes ECM stiffening, has emerged as a prominent hallmark of poor disease prognosis and cancer metastasis. In addition to that, cancer cells are also known for their highly reprogrammed metabolism. The objective of this study was to establish a relationship between increased stiffness of tumor microenvironment and metabolism in cancer cells. A deterministic analytical model has been constructed to demonstrate the mechanoadaptation of metabolism in cancer cells. This mathematical model shows that increased stiffness has a positive effect on HIF1α accumulation under hypoxia. As HIF1α promotes the Warburg effect, this result highlights the potential link between Tumor mechanics and metabolism.