Huels, David J., Ridgway, Rachel A., Radulescu, Sorina, Leushacke, Marc, Campbell, Andrew D., Biswas, Sujata, Leedham, Simon, Serra, Stefano, Chetty, Runjan, Moreaux, Guenievre, Parry, Lee  ORCID: https://orcid.org/0000-0002-4467-9196, Matthews, James, Song, Fei, Hedley, Ann, Kalna, Gabriela, Ceteci, Fatih, Reed, Karen R. ORCID: https://orcid.org/0000-0002-7467-1718, Meniel, Valerie S., Maguire, Aoife, Doyle, Brendan, Soderberg, Ola, Barker, Nick, Watson, Alastair, Larue, Lionel, Clarke, Alan R. ORCID: https://orcid.org/0000-0002-4281-426X and Sansom, Owen J.
2015.
E-cadherin can limit the transforming properties of activating β‐catenin mutations.
EMBO Journal
34
(18)
, pp. 2321-2333.
10.15252/embj.201591739
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Abstract
Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in b-catenin (CTNNB1). We have compared the dynamics and the potency of b-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of b-catenin took much longer to achieve Wnt deregulation and acquire a crypt-progenitor cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of b-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of b-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin: b-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of b-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of b-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated b-catenin.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Biosciences Research Institutes & Centres > European Cancer Stem Cell Research Institute (ECSCRI) |
| Additional Information: | This is an open access article under the terms of the CC-BY 4.0 license |
| Publisher: | EMBO Press |
| ISSN: | 0261-4189 |
| Date of First Compliant Deposit: | 30 March 2016 |
| Date of Acceptance: | 1 July 2015 |
| Last Modified: | 04 Apr 2025 21:20 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/75607 |
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