TAT-Cx43 266-283 impairs metabolic plasticity in glioma stem cells in vitro and in vivo

Glioblastoma is the most aggressive primary brain cancer, with a median survival of 1 to 2 years. These tumours contain glioma stem cells (GSCs), which are highly tumorigenic, resistant to conventional therapies, and exhibit metabolic plasticity to adapt to challenging environments. GSCs can be specifically targeted by a short cell-penetrating peptide based on connexin43 (Cx43) (TAT-Cx43) that reduces tumour growth and increases survival in preclinical models via c-Src inhibition. Because several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells, we investigated the effect of TAT-Cx43 on GSC metabolism and metabolic plasticity. Here we show that TAT-Cx43 decreases GSC glucose uptake and oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on neuron or astrocyte metabolism. GSC changes were mediated by decreased hexokinase (HK) activity and aberrant mitochondrial localization, ultrastructure and function. Moreover, TAT-Cx43 reduced GSC growth and survival under different nutrient availability conditions by impairing the metabolic plasticity needed to exploit glucose as an energy source in the absence of other nutrients. Finally, GSCs intracranially implanted into mice together with TAT-Cx43 showed decreased levels of important targets for cancer therapy, such as HK-2 and glucose transporter 3 (GLUT-3), evidencing the reduced ability of treated GSCs to survive in challenging environments. Our results confirm the value of TAT-Cx43 for glioma therapy alone or in combination with therapies whose resistance relies on metabolic adaptation. More importantly, these results allow us to conclude that the advantageous metabolic plasticity of GSCs is a targetable vulnerability in malignant gliomas.