Dynamic links between mechanical forces and metabolism shape the tumor milieu

Cell function relies on the spatiotemporal dynamics of metabolic reactions. In all physiopathological processes of tissues, mechanical forces impact the structure and function of membranes, enzymes, organelles and regulators of metabolic gene programs, thus regulating cell metabolism. In turn, metabolic pathways feedback impacts the physical properties of cell and tissues. Hence, metabolism and tissue mechanics are dynamically intertwined and continuously interact. Cancer is akin to an ecosystem, comprising tumor cells and various subpopulations of stromal cells embedded in an altered extracellular matrix. The progression of cancer, from initiation to advanced stage and metastasis, is driven by genetic mutations and crucially influenced by physical and metabolic alterations in the tumor microenvironment. These alterations also play a pivotal role in cancer cells evasion from immune surveillance and in developing resistance to treatments. Here, we highlight emerging evidence showing that mechano-metabolic circuits in cancer and stromal cells regulate multiple processes crucial for tumor progression and discuss potential approaches to improve therapeutic treatments by interfering with these circuits.