Loss of the tumor suppressor p53 generates a signaling gradient that drives epithelial clonal expansion.

Although tumor protein p53 (TP53) mutations are among the most common lesions in epithelial cancers, how p53 loss drives unrestrained clonal expansion remains unclear. Working with mouse epidermis, we found that p53 suppresses clonal expansion by limiting progenitor self-renewal. Integrating chromatin immunoprecipitation sequencing, transcriptional analyses, and genetic screens, we identified a p53-dependent network controlling progenitor renewal and differentiation, in which secreted frizzled-related protein 1 (Sfrp1), low-density lipoprotein receptor-related protein 1 (Lrp1), and ubiquitin-specific peptidase 22 (Usp22) were direct targets of p53 and the most genetically upstream components. Their suppression after p53 loss generated a radial gradient of Wnt activity across mutant clones. Genetic manipulation showed that a Wnt activity gradient, rather than uniform elevation, was associated with sustained clonal expansion. These findings identify spatial organization as a determinant of clonal behavior and a mechanism by which TP53 inactivation drives tissue colonization.