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

Masalmeh, R. H. A.; Dawson, J. C.; Garcia, V. A.; Muir, M. T.; Carter, R. N.; Hardingham, G.; Davies, C.; Graham, R.; von Kriegsheim, A.; Marques Junior, J.; Pednekar, C.; Pollard, S. M.; Carragher, N. O.; Brunton, V. G.; Frame, M. C.

doi:10.1101/2024.12.11.627900

bioRxiv · 10.1101/2024.12.11.627900

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

Masalmeh, R. H. A.·Dawson, J. C.·Garcia, V. A.·Muir, M. T.·Carter, R. N.·Hardingham, G.·Davies, C.·Graham, R.·von Kriegsheim, A.·Marques Junior, J.·Pednekar, C.·Pollard, S. M.·Carragher, N. O.·Brunton, V. G.·Frame, M. C.

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Abstract

Glycolysis and the TCA cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). We show that focal adhesion kinase (FAK), a mediator of integrin-ECM signalling, is driving cellular energetics in a stem cell model of glioblastoma (GBM). FAK gene deletion inhibits both glycolysis and glutamine oxidation, with increased mitochondrial fragmentation and elevated phosphorylation of the mitochondrial protein MTFR1L at S235. Simultaneously, FAK loss causes a mesenchymal to epithelial transition, enhanced acto-myosin contractility as shown by phospho-myosin light chain (p-MLC S19) and impaired cell migration/invasiveness. Rho-kinase (ROCK) inhibitors suppress p-MLC (S19) and restore glutamine oxidation and elongation of mitochondria. Thus, FAK is a key regulator of both glycolysis and glutamine oxidation mediated by acto-myosin contractility that controls both cell and mitochondrial morphology. Moreover, FAK-dependent cellular energetics are coincident properties with GBM stem cell migration, invasiveness and tumour growth in vivo.

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Masalmeh, R. H. A., Dawson, J. C., Garcia, V. A., Muir, M. T., Carter, R. N., Hardingham, G., Davies, C., Graham, R., von Kriegsheim, A., Marques Junior, J., Pednekar, C., Pollard, S. M., Carragher, N. O., Brunton, V. G., Frame, M. C.. 2024-12-12. FAK modulates glioblastoma stem cell energetics via actomyosin contractility: regulation of glycolysis and mitochondrial function. https://doi.org/10.1101/2024.12.11.627900

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