p53: defender of lineage fidelity and foe of plasticity in cancer and regeneration.

Although p53 plays a vital role in tumor suppression, the molecular programs underlying its tumor suppressor function remain incompletely understood. Recent work coupling genetically engineered mouse models and single-cell RNA sequencing has illuminated new aspects of p53 function in governing cell state changes. During both lung adenocarcinoma suppression and lung injury repair, p53 acts in a plastic transitional cell state to drive alveolar type 1 cell differentiation, while p53 deficiency causes transitional cell persistence and cancer progression or tissue damage. New insights into p53 function in injury repair in other tissues have also emerged, including in injury-induced intestinal revival stem cells. These studies underscore the importance of p53 in specific plastic states, where it coordinately enforces differentiation and restrains lineage infidelity during tissue healing and cancer suppression.