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While sporadic human colon adenomas exhibit features of top-down tumorigenesis, their biological determinants remain elusive. Here, using a Smad4 loss-of-function and \u03b2-catenin gain-of-function (Smad4\n                    <jats:sup>LOF<\/jats:sup>\n                    :\u03b2-catenin\n                    <jats:sup>GOF<\/jats:sup>\n                    ) mouse model, we demonstrate that dedifferentiation-derived oncogenic stem cells sustain tumorigenesis more effectively than endogenous mutant stem cells harboring the mutation. The dedifferentiating villi epithelial cells showed early expression of CD44 and\n                    <jats:italic>Lgr5<\/jats:italic>\n                    , supporting oncogenic stemness. Aberrant Notch signaling in the villi epithelium was also detected at the onset of dedifferentiation, suggesting its contribution to dedifferentiation. Single-cell RNA sequencing revealed a distinct population of dedifferentiation-derived stem cells enriched for proliferative, metabolic, and mouse embryonic stem cell-like gene signatures, consistent with enhanced plasticity and tumorigenic potential. These mutant cells exhibited growth factor independence, indicating a capacity for niche-independent proliferation and metabolic adaptation to sustain tumor growth. These findings identify dedifferentiation-driven stemness, aberrant Notch activation, and metabolic plasticity as cooperative mechanisms that promote top-down intestinal tumorigenesis. This study provides insight into how oncogenic dedifferentiation contributes to tumor heterogeneity and persistence and has implications for therapeutic resistance in colorectal cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08669-2","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T21:14:37Z","timestamp":1776460477000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dedifferentiation-driven oncogenic stemness promotes tumor-sustaining adaptability in the intestinal epithelium"],"prefix":"10.1038","volume":"17","author":[{"given":"Kylee","family":"Zgeib","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0408-055X","authenticated-orcid":false,"given":"Thompson","family":"Hui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Hashemi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shima","family":"Nejati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amartya","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atharva","family":"Inamdar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahlia","family":"Matouba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7822-5950","authenticated-orcid":false,"given":"Binfeng","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3083-8405","authenticated-orcid":false,"given":"Ansu O.","family":"Perekatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"8669_CR1","first-page":"233","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. 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