title: A hypermorphic epithelial β-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations.
abstract: Activation of the Wnt/β-catenin pathway occurs in the vast majority of colorectal cancers. However, the outcome of the disease varies markedly from individual to individual, even within the same tumor stage. This heterogeneity is governed to a great extent by the genetic make-up of individual tumors and the combination of oncogenic mutations. In order to express throughout the intestinal epithelium a degradation-resistant β-catenin (Ctnnb1), which lacks the first 131 amino acids, we inserted an epitope-tagged ΔN(1-131)-β-catenin-encoding cDNA as a knock-in transgene into the endogenous gpA33 gene locus in mice. The resulting gpA33(ΔN-Bcat) mice showed an increase in the constitutive Wnt/β-catenin pathway activation that shifts the cell fate towards the Paneth cell lineage in pre-malignant intestinal epithelium. Furthermore, 19% of all heterozygous and 37% of all homozygous gpA33(ΔN-Bcat) mice spontaneously developed aberrant crypt foci and adenomatous polyps, at frequencies and latencies akin to those observed in sporadic colon cancer in humans. Consistent with this, the Wnt target genes, MMP7 and Tenascin-C, which are most highly expressed in benign human adenomas and early tumor stages, were upregulated in pre-malignant tissue of gpA33(ΔN-Bcat) mice, but those Wnt target genes associated with excessive proliferation (i.e. Cdnn1, myc) were not. We also detected diminished expression of membrane-associated α-catenin and increased intestinal permeability in gpA33(ΔN-Bcat) mice in challenge conditions, providing a potential explanation for the observed mild chronic intestinal inflammation and increased susceptibility to azoxymethane and mutant Apc-dependent tumorigenesis. Collectively, our data indicate that epithelial expression of ΔN(1-131)-β-catenin in the intestine creates an inflammatory microenvironment and co-operates with other mutations in the Wnt/β-catenin pathway to facilitate and promote tumorigenesis.
authors.affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia michael.buchert@onjcri.org.au klaus-peter.janssen@lrz.tum.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchert
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Rohde
authors.affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
authors.forename: Moritz
authors.initials: M
authors.lastname: Eissmann
authors.affiliation: Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
authors.forename: Niall
authors.initials: N
authors.lastname: Tebbutt
authors.affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Williams
authors.affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Chin Wee
authors.initials: CW
authors.lastname: Tan
authors.affiliation: Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Owen
authors.affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hirokawa
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gnann
authors.affiliation: Inserm U1109, MN3T team, 3 Av. Molière, Strasbourg 67200, France LabEx Medalis, Université de Strasbourg, Strasbourg 67200, France Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg 67200, France.
authors.forename: Gertraud
authors.initials: G
authors.lastname: Orend
authors.affiliation: University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Gayle
authors.initials: G
authors.lastname: Orner
authors.affiliation: Texas A&M Health Science Center, Center for Epigenetics and Disease Prevention, Houston, TX 77030-3303, USA.
authors.forename: Rod H
authors.initials: RH
authors.lastname: Dashwood
authors.affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Joan K
authors.initials: JK
authors.lastname: Heath
authors.affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany michael.buchert@onjcri.org.au klaus-peter.janssen@lrz.tum.de.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
mesh_terms: D018256:Adenomatous Polyps / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001397:Azoxymethane; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003111:Colonic Polyps / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019063:Tenascin / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D016207:Cytokines; D019063:Tenascin; D051176:beta Catenin; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; D001397:Azoxymethane
keywords: Colorectal cancer; GpA33; Inflammation; Mouse models