Disruption of the crypt niche promotes outgrowth of mutated colorectal tumor stem cells Journal Article
| Authors: | Klingler, S.; Hsu, K. S.; Hua, G.; Martin, M. L.; Adileh, M.; Baslan, T.; Zhang, Z.; Paty, P. B.; Fuks, Z.; Brown, A. M. C.; Kolesnick, R. |
| Article 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 (AOMDSS) 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. © 2022, Klingler et al. |
| Keywords: | controlled study; unclassified drug; gene mutation; human cell; nonhuman; colorectal cancer; animal cell; mouse; phenotype; animal tissue; animal experiment; animal model; in vivo study; in vitro study; carcinogenesis; stem cell; ex vivo study; wnt protein; stem cell niche; cell separation; g protein coupled receptor; intestine crypt; wnt signaling; orthology; dextran sulfate; gain of function mutation; human; male; article; basal lamina; azoxymethane; leucine rich repeat containing g protein coupled receptor 5; colonic epithelial stem cell; dextran sulfate sodium-induced colitis; adaptive oncogenesis |
| Journal Title: | JCI Insight |
| Volume: | 7 |
| Issue: | 5 |
| ISSN: | 2379-3708 |
| Publisher: | Amer Soc Clinical Investigation Inc |
| Date Published: | 2022-03-08 |
| Start Page: | e153793 |
| Language: | English |
| DOI: | 10.1172/jci.insight.153793 |
| PUBMED: | 35260534 |
| PROVIDER: | scopus |
| PMCID: | PMC8983138 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2022 -- Source: Scopus |
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