The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival

The tumor microenvironment imposes diverse metabolic challenges to cancer cells. Overcoming these challenges is essential for survival, proliferation, and dissemination. However, how cancer cells cope with the harsh environment and how the different coexisting stresses affect the tumor in vivo is unknown. Recently, Groessl, Kalis and colleagues published their findings in Science showing that acidosis outweighs all other stresses and plays a major role in the adaptation to them. Mechanistically, acidosis inhibits the ERK-DRP1 pathway, resulting in mitochondria elongation, which triggers a metabolic shift from glycolysis to oxidative phosphorylation. These findings highlight the plasticity of cancer cell mitochondria and refute the previous belief that cancer mitochondria are inherently dysfunctional. Indeed, inhibition of mitochondrial fusion or oxidative phosphorylation in acidic tumors is sufficient to promote cell death. Thus, enhancing respiration under acidosis comes to light as an essential metabolic adaptation to cancer survival and proliferation and targeting how cancer cells adapt to acidosis emerges as a new avenue for therapy.