title: E-cadherin can limit the transforming properties of activating β-catenin mutations.
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 β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-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 β-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of β-catenin mutation to differentially transform the SI versus the colon correlated with higher expression of E-cadherin and a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction in E-cadherin synergised with an activating mutation of β-catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of β-catenin that is required to drive transformation, and E-cadherin can act as a buffer to sequester mutated β-catenin.
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Huels
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Sorina
authors.initials: S
authors.lastname: Radulescu
authors.affiliation: A∗STAR Institute of Medical Biology, Singapore City, Singapore.
authors.forename: Marc
authors.initials: M
authors.lastname: Leushacke
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.affiliation: Gastrointestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics University of Oxford, Oxford, UK Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, Headington, UK.
authors.forename: Sujata
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Gastrointestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics University of Oxford, Oxford, UK Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford, Headington, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Leedham
authors.affiliation: Department of Pathology, University Health Network/Toronto Medical Laboratories, Toronto, Canada.
authors.forename: Stefano
authors.initials: S
authors.lastname: Serra
authors.affiliation: Department of Pathology, University Health Network/Toronto Medical Laboratories, Toronto, Canada.
authors.forename: Runjan
authors.initials: R
authors.lastname: Chetty
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Guenievre
authors.initials: G
authors.lastname: Moreaux
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Parry
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
authors.forename: James
authors.initials: J
authors.lastname: Matthews
authors.affiliation: Institute of Physiology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Hedley
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Fatih
authors.initials: F
authors.lastname: Ceteci
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Reed
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Meniel
authors.affiliation: Department of Histopathology, Trinity College Dublin St James's Hospital, Dublin, Ireland.
authors.forename: Aoife
authors.initials: A
authors.lastname: Maguire
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK Department of Histopathology, Trinity College Dublin St James's Hospital, Dublin, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Doyle
authors.affiliation: Department of Immunology, Genetics and Pathology Science for Life Laboratory, BMC Uppsala University, Uppsala, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Söderberg
authors.affiliation: A∗STAR Institute of Medical Biology, Singapore City, Singapore.
authors.forename: Nick
authors.initials: N
authors.lastname: Barker
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Watson
authors.affiliation: Institut Curie, CNRS UMR3347 INSERM, U1021 Equipe labellisée - Ligue Nationale contre le Cancer, Orsay, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK o.sansom@beatson.gla.ac.uk.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D015820:Cadherins; D009363:Neoplasm Proteins; D051176:beta Catenin
keywords: APC; E‐cadherin; colorectal cancer; β‐catenin