FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation

Glycolysis and the tricarboxylic acid cycle (TCA) cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). However, the mechanisms by which the ECM engagement reprograms core energy metabolism is still unknown. We showed that the canonical cell−ECM adhesion protein focal adhesion kinase (FAK, also known as PTK2) and, specifically, its kinase activity, is driving cellular energetics. Using a mouse stem cell model of glioblastoma, we showed that deletion of the FAK gene simultaneously inhibits glycolysis and glutamine oxidation, increases mitochondrial fragmentation, elevates phosphorylation of the mitochondrial protein MTFR1L at serine residue 235 (S235) and triggers a mesenchymal-to-epithelial transition. These metabolic and structural changes arise through altered contractility of actomyosin, as shown by myosin light chain type II (MYL2, also known as MLC2) phosphorylated (p) at S19. This process can be reversed by Rho-kinase (ROCK) inhibitors revealing mechanotransduction pathway control of both mitochondrial dynamics and glutamine oxidation. FAK-dependent metabolic programming is associated with regulation of cell migration, invasive capacity and tumour growth in vivo. Our work describes a previously unrecognised FAK–ROCK axis that couples mechanical cues to the rewiring of energy metabolism, linking cell shape, mitochondrial function and malignant behaviour.