{"doi":"10.1172/jci.insight.153793","title":"Disruption of the crypt niche promotes outgrowth of mutated colorectal tumor stem cells","abstract":"Recent data establish a logarithmic expansion of leucine rich repeat containing G protein coupled receptor 5-positive (Lgr5+) colonic epithelial stem cells (CESCs) in human colorectal cancer (CRC). Complementary studies using the murine 2-stage azoxymethane-dextran 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+ CESCs with gain-of-function Wnt mutations orthologous to human CRC driver mutations. We posit CRC originates by niche injury-induced outgrowth of normally suppressed mutated stem cells, consistent with models of adaptive oncogenesis.","journal":"JCI Insight","year":2022,"id":271531,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9401,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":298698,"name":"Kuo‐Shun Hsu","orcid":"0000-0003-4826-506X","position":1,"is_corresponding":false},{"id":936933,"name":"Guoqiang Hua","orcid":"0000-0001-9274-8136","position":2,"is_corresponding":false},{"id":236118,"name":"M. Laura Martín","orcid":"0000-0001-9359-5856","position":3,"is_corresponding":false},{"id":524837,"name":"Mohammad Adileh","orcid":null,"position":4,"is_corresponding":false},{"id":305290,"name":"Timour Baslan","orcid":"0000-0001-5674-6432","position":5,"is_corresponding":false},{"id":473953,"name":"Zhigang Zhang","orcid":"0000-0001-8965-223X","position":6,"is_corresponding":false},{"id":239556,"name":"Philip B. Paty","orcid":"0000-0002-7045-2112","position":7,"is_corresponding":false},{"id":354854,"name":"Zvi Fuks","orcid":null,"position":8,"is_corresponding":false},{"id":936934,"name":"Anthony M.C. Brown","orcid":"0000-0001-5129-1635","position":9,"is_corresponding":false},{"id":353754,"name":"Richard Kolesnick","orcid":"0000-0002-4914-2945","position":10,"is_corresponding":false},{"id":936932,"name":"Stefan Klingler","orcid":"0000-0003-4929-1913","position":0,"is_corresponding":true}],"reference_count":97,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:27:39.717534Z","pmid":"35260534","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}