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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 (\n                    <jats:italic toggle=\"yes\">Sfrp1<\/jats:italic>\n                    ), low-density lipoprotein receptor\u2013related protein 1 (\n                    <jats:italic toggle=\"yes\">Lrp1<\/jats:italic>\n                    ), and ubiquitin-specific peptidase 22 (\n                    <jats:italic toggle=\"yes\">Usp22<\/jats:italic>\n                    ) 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\n                    <jats:italic toggle=\"yes\">TP53<\/jats:italic>\n                    inactivation drives tissue colonization.\n                  <\/jats:p>","DOI":"10.1126\/science.aed3065","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:00:47Z","timestamp":1790877647000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Loss of the tumor suppressor p53 generates a signaling gradient that drives epithelial clonal expansion"],"prefix":"10.1126","volume":"394","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8945-5930","authenticated-orcid":true,"given":"Qiwen","family":"Gan","sequence":"first","affiliation":[{"name":"Department of Stem Cell Biology and Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 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