A Spotlight on Oxidative Metabolism in Oncogenic Transformation and Cell Competition.

Abstract

Normal tissues actively employ a phenomenon called cell competition to drive the elimination and replacement of less fit loser cells by fitter winner cells. This quality control mechanism promotes tissue health by favoring the selective expansion of fitter cells. Indeed, through cell competition many mutant cells are eliminated from tissues by fitter normal cells. However, some oncogenic mutations can turn cells into supercompetitors that outcompete normal cells, promoting tumorigenic growth and metastasis. Several cellular stresses have been associated with the loser status such as oxidative stress, DNA damage responses, unfolded protein response, and mitochondrial dysfunction. By affecting these pathways, metabolism and dietary choices can regulate cellular fitness and cell competition. However, how these pathways affect competitive interactions in vivo, during the early establishment of mutant clones, is relatively little understood. Recent work from Hemalatha and colleagues introduces real-time fluorescence ratio metric imaging of NAD(P)H and FAD to investigate cellular redox status-live and over time, at a single-cell level-as cells compete in the mouse epidermis. Their work demonstrates that redox status changes dynamically during competition between cells carrying oncogenic mutations. It further shows that drugs that modulate mitochondrial metabolism and cellular redox are strong modulators of cell competition. The introduction of live redox imaging will prove a powerful tool to further dissect how metabolic states affect cell competition in normal physiology and in tumorigenesis.