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Complementary studies using the murine 2-stage azoxymethane\u2013dextran sulfate sodium (AOM-DSS) colitis-associated tumor model indicate early acquisition of Wnt pathway mutations drives CESC expansion during adenoma progression. Here, subdivision of the AOM-DSS model into in vivo and in vitro stages revealed DSS induced physical separation of CESCs from stem cell niche cells and basal lamina, a source of Wnt signals, within hours, disabling the stem cell program. While AOM delivery in vivo under non-adenoma-forming conditions yielded phenotypically normal mucosa and organoids derived thereof, niche injury ex vivo by progressive DSS dose escalation facilitated outgrowth of Wnt-independent dysplastic organoids. These organoids contained 10-fold increased Lgr5\n                    <jats:sup>+<\/jats:sup>\n                    CESCs with gain-of-function Wnt mutations orthologous to human CRC driver mutations. We posit CRC originates by niche injury\u2013induced outgrowth of normally suppressed mutated stem cells, consistent with models of adaptive oncogenesis.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.153793","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T14:00:56Z","timestamp":1646661656000},"source":"Crossref","is-referenced-by-count":12,"title":["Disruption of the crypt niche promotes outgrowth of mutated colorectal tumor stem cells"],"prefix":"10.1172","volume":"7","author":[{"given":"Stefan","family":"Klingler","sequence":"first","affiliation":[{"name":"Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Shun","family":"Hsu","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New 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