Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation

As humans age, normal tissues, such as the esophageal epithelium, become a patchwork of mutant clones. Some mutations are under positive selection, conferring a competitive advantage over wild-type cells. We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the transgenic mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensitive to LDIR and outcompete wild-type cells following exposure. Remarkably, combining antioxidant treatment and LDIR reverses this effect, promoting wild-type cell proliferation and p53 mutant differentiation, reducing the p53 mutant population. Thus, p53-mutant cells can be depleted from the normal esophagus by redox manipulation, showing that external interventions may be used to alter the mutational landscape of an aging tissue. [Display omitted] •Cell tracking shows low-dose ionizing radiation drives differentiation in esophagus•Low-dose radiation acts via redox stress without activating the DNA repair pathway•p53 mutant cells do not differentiate after irradiation and outcompete normal cells•Antioxidant plus radiation depletes p53 mutant cells by improving normal cell fitness Normal human esophagus contains p53 mutant progenitors. Fernandez-Antoran and colleagues show that p53 mutant progenitors outcompete their wild-type neighbors after low-dose ionizing radiation. This effect is reversed by antioxidant pretreatment. p53 mutant cells can be displaced from normal tissues via the improvement of the competitive fitness of wild-type progenitors.