Metabolic plasticity in cancer cells : involvement in the processes of proliferation and response to radiotherapy

While pioneering studies suggested that enhanced glycolysis, a hallmark of cancer, was caused by an irreversible impairment in mitochondrial respiration, more recent data reported functional mitochondrial activity in many cancer cells. In this thesis, we thus intended to investigate whether metabolic modulations could improve the therapeutic outcome of cancer. We found that dichloroacetate, a new clinically tested compound, induced a switch of glycolytic cancer cells to a more oxidative phenotype, and decreased tumor cell proliferation through a decrease in the activity of the pentose phosphate pathway. In a second part of this work, we investigated whether targeting mitochondrial respiration with H2S, the last gaseous transmitter identified in mammals, improved tumor response to radiotherapy. By rapidly alleviating hypoxia inside solid tumors, the single injection of a H2S donor increased the radioresponse of cancer in mice. Overall, our thesis work emphasizes the ability of cancer cells to remodel their energetic metabolism in response to external stimuli and supports that both glycolysis and oxidative phosphorylation are attractive targets for cancer therapy.