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

TY - JOUR

T1 - Chir99021 and Valproic acid reduce the proliferative advantage of Apc mutant cells

AU - Langlands, Alistair J.

AU - Carroll, Thomas D.

AU - Chen, Yu

AU - Nathke, Inke

N1 - We would like to thank members of the Näthke laboratory for general assistance and helpful discussions with particular thanks to Ian Newton for technical help. Microscopy and image analysis support was provided by the Dundee Light Microscopy and Tissue Imaging Facility funded by the Welcome Trust Technology Platform award (097945/B/11/Z) and Welcome trust award (101468/Z/13/Z). We are grateful for help from Dr. Rosie Clarke of the Flow Cytometry and Cell Sorting Facility at the University of Dundee, which is supported by Wellcome Trust award (097418/Z/11/Z). This work was supported by a program grant from Cancer Research UK to I.S.N (C430/A11243) that supported A.J.L., an MRC studentship that supported T.D.C. and a project award from NC3R (NC/M001156/1) that supported Y.C.

PY - 2018/2/15

Y1 - 2018/2/15

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85042174896

U2 - 10.1038/s41419-017-0199-9

DO - 10.1038/s41419-017-0199-9

M3 - Article

C2 - 29449562

SN - 2041-4889

VL - 9

SP - 1

EP - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

M1 - 255

ER -