Metabolic reprogramming and substrate preference in cancers: a hypothesis

Cancer is a complex pathology, whose burden is growing worldwide. It appears that our vision considering cancer cells as a uniform population is partial: cancer cells evolve in time, building up mutations to adapt to their environment. They become able to evade cellular controls, and then immune response. A hallmark of cancer adaptation ability is metabolic reprogramming. Consistently, inhibitors of glycolysis, and of fatty acid uptake into the mitochondria are promising anticancer agents. The classical Warburg effect has been revised in the last years, and it appears that the increased glucose requirement of cancer cells is related to the shifting of glucose flux to the pentose phosphate pathway, to obtain trioses, NADPH and ribose 5-P, in face of increased lactate production and oxygen consumption (Vander Heiden, et al. 2009, Cossu, et al. 2020). Typically, metastasizing cancer cells heavily rely on the oxidative phosphorylation. In particular, apparently encephalic tumours preferentially utilize glucose and glutamine as nutrients, as opposed to tumours in the rest of the body, which preferentially catabolize fatty acids. This implies an obligatory role for functional mitochondria, where the beta-oxidation occurs. A shift toward the oxidative metabolism is also a main driver of chemotherapy resistance. The expression of the electron transfer chain complexes I to IV and the F1Fo-ATP synthase was reported out of the mitochondria, in plasma membrane derived structures (Ravera, et al. 2021), and also on the surface of cancer cells. It is tempting to presume that the difference in substrate preference is due to the diverse respiring structures in the brain, above or below the vascular Willis circle. A future therapeutic vision may hopefully involve targeting the tumour cell metabolism at multiple levels. It will then be crucial to target tumour cells at the level of their metabolism, which would be tumour- and location-specific.