FAK modulates glioblastoma stem cell energetics via actomyosin contractility: regulation of glycolysis and mitochondrial function

Glycolysis and the TCA cycle are commonly reprogrammed to fulfil the bioenergetic and biosynthetic demands of cancer cells. Although the extracellular matrix is known to influence glycolysis and the TCA cycle, it is not well understood how specific adhesion proteins and their downstream effectors contribute to metabolic changes and to the mitigation of metabolic stress. Here, we report that the canonical focal adhesion protein FAK is required for optimal cellular energetics through both glycolysis and the TCA cycle in a transformed neural stem cell model of glioblastoma. Mechanistically, FAK promotes the TCA cycle by keeping myosin II activity low in cells with a mesenchymal-like morphology. Genetic deletion of FAK induces an epithelial-like morphology with elevated myosin II activity as evidenced by phospho-myosin light chain accumulation at cell-cell contacts. In this context these cells have impaired glycolysis and TCA cycle flux that is accompanied by shortening of mitochondria fragments. Treating FAK depleted cells with multiple Rho-kinase (ROCK) inhibitors restores efficient TCA cycle flux, mitochondrial morphology, cells’ mesenchymal nature and viability. Phenotypically, the reduction in cell energetics after FAK depletion is accompanied by reduced cancer cell motility and invasiveness in vitro and suppression of tumour growth and increased survival in an orthotopic murine model. We demonstrate a novel role for FAK as an adhesion protein which can modulate cellular energetics and mitochondria morphology in glioblastoma stem cells with profound consequences for cancer-associated cell phenotypes and tumour growth in vivo.