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A 'just-right' signalling model proposes that<jats:italic>Apc<\/jats:italic>mutations stimulate optimal, but not excessive Wnt signalling, resulting in a growth advantage of<jats:italic>Apc<\/jats:italic>mutant over wild-type cells. Reversal of this growth advantage constitutes a potential therapeutic approach. We utilised intestinal organoids to compare the growth of<jats:italic>Apc<\/jats:italic>mutant and wild-type cells. Organoids derived from<jats:italic>Apc<\/jats:italic><jats:sup><jats:italic>Min\/+<\/jats:italic><\/jats:sup>mice recapitulate stages of intestinal polyposis in culture. They eventually form spherical cysts that reflect the competitive growth advantage of cells that have undergone loss of heterozygosity (LOH). We discovered that this emergence of cysts was inhibited by Chiron99021 and Valproic acid, which potentiates Wnt signalling. Chiron99021 and Valproic acid restrict the growth advantage of<jats:italic>Apc<\/jats:italic>mutant cells while stimulating that of wild-type cells, suggesting that excessive Wnt signalling reduces the relative fitness of<jats:italic>Apc<\/jats:italic>mutant cells. As a proof of concept, we demonstrated that Chiron99021-treated<jats:italic>Apc<\/jats:italic>mutant organoids were rendered susceptible to TSA-induced apoptosis, while wild-type cells were protected.<\/jats:p>","DOI":"10.1038\/s41419-017-0199-9","type":"journal-article","created":{"date-parts":[[2018,2,15]],"date-time":"2018-02-15T08:09:33Z","timestamp":1518682173000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells"],"prefix":"10.1038","volume":"9","author":[{"given":"Alistair J.","family":"Langlands","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas D.","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2420-4385","authenticated-orcid":false,"given":"Inke","family":"N\u00e4thke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,2,15]]},"reference":[{"key":"199_CR1","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1053\/j.gastro.2012.08.031","volume":"143","author":"HF Farin","year":"2012","unstructured":"Farin, H. 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