Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells

Alistair J. Langlands, Thomas D. Carroll, Yu Chen, Inke Nathke (Lead / Corresponding author)

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Abstract

More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A ‘just-right’ signalling model proposes that Apc mutations stimulate optimal, but not
excessive Wnt signalling, resulting in a growth advantage of Apc mutant over wild-type cells. Reversal of this growth advantage constitutes a potential therapeutic approach. We utilized intestinal organoids to compare the growth of Apc mutant and wild-type cells. Organoids derived from ApcMin/+ mice re-capitulate 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 Apc mutant cells while stimulating that of wild-type cells, suggesting that excessive Wnt signalling reduces the relative fitness of Apc mutant cells. As a proof of concept, we demonstrated that Chiron99021–treated Apc mutant organoids were rendered susceptible to TSA-induced apoptosis, while wild-type cells were protected.
Original languageEnglish
Article number255
Pages (from-to)1-10
Number of pages10
JournalCell Death and Disease
Volume9
DOIs
Publication statusPublished - 15 Feb 2018

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