title: Hemidesmosome integrity protects the colon against colitis and colorectal cancer.
abstract: Epidemiological and clinical data indicate that patients suffering from IBD with long-standing colitis display a higher risk to develop colorectal high-grade dysplasia. Whereas carcinoma invasion and metastasis rely on basement membrane (BM) disruption, experimental evidence is lacking regarding the potential contribution of epithelial cell/BM anchorage on inflammation onset and subsequent neoplastic transformation of inflammatory lesions. Herein, we analyse the role of the α6β4 integrin receptor found in hemidesmosomes that attach intestinal epithelial cells (IECs) to the laminin-containing BM.
  
  
  
  We developed new mouse models inducing IEC-specific ablation of α6 integrin either during development (α6ΔIEC) or in adults (α6ΔIEC-TAM).
  
  
  
  Strikingly, all α6ΔIECmutant mice spontaneously developed long-standing colitis, which degenerated overtime into infiltrating adenocarcinoma. The sequence of events leading to disease onset entails hemidesmosome disruption, BM detachment, IL-18 overproduction by IECs, hyperplasia and enhanced intestinal permeability. Likewise, IEC-specific ablation of α6 integrin induced in adult mice (α6ΔIEC-TAM) resulted in fully penetrant colitis and tumour progression. Whereas broad-spectrum antibiotic treatment lowered tissue pathology and IL-1β secretion from infiltrating myeloid cells, it failed to reduce Th1 and Th17 response. Interestingly, while the initial intestinal inflammation occurred independently of the adaptive immune system, tumourigenesis required B and T lymphocyte activation.
  
  
  
  We provide for the first time evidence that loss of IECs/BM interactions triggered by hemidesmosome disruption initiates the development of inflammatory lesions that progress into high-grade dysplasia and carcinoma. Colorectal neoplasia in our mouse models resemble that seen in patients with IBD, making them highly attractive for discovering more efficient therapies.
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Adèle
authors.initials: A
authors.lastname: De Arcangelis
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.|Current address: F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Hussein
authors.initials: H
authors.lastname: Hamade
authors.affiliation: Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.|Inserm, U1109, MNT3 Team, Strasbourg, France.|Current address: Department of Functional Genomics and Cancer, IGBMC, Illkirch, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Alpy
authors.affiliation: CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Université de Lille, Lille, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Normand
authors.affiliation: Inserm, Université de Lille, CHRU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bruyère
authors.affiliation: Université de Strasbourg, Strasbourg, France.|Inserm, U1109, MNT3 Team, Strasbourg, France.|LabEx Medalis, Université de Strasbourg, Strasbourg, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lefebvre
authors.affiliation: Inserm, U1109, MNT3 Team, Strasbourg, France.|CHRU Strasbourg, Hôpital de Hautepierre, Service d'anatomo-pathologie, Strasbourg, France.|Current address: Département de Pathologie, Institut Bergonie, Bordeaux, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Méchine-Neuville
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Siebert
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Pfister
authors.affiliation: UMR1319-MICALIS Institute, INRA, AgroParisTech,Université Paris-Saclay, Jouy-en-Josas, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lepage
authors.affiliation: Université de Strasbourg, Strasbourg, France.|CNRS, UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Laquerriere
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembele
authors.affiliation: CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Université de Lille, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Delanoye-Crespin
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.|Current address: NORLUX Neuro-Oncology Laboratory, CRP-Santé, Luxembourg.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rodius
authors.affiliation: Institut Curie, Paris, France.|CNRS, UMR 144, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robine
authors.affiliation: Université de Strasbourg, Strasbourg, France.|Inserm, U1109, MNT3 Team, Strasbourg, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Kedinger
authors.affiliation: Inserm, Université de Lille, CHRU Lille, UMR-S 1172-Jean-Pierre Aubert Research Center, Lille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.affiliation: Université de Strasbourg, Strasbourg, France.|Inserm, U1109, MNT3 Team, Strasbourg, France.|LabEx Medalis, Université de Strasbourg, Strasbourg, France.|Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Simon-Assmann
authors.affiliation: CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Université de Lille, Lille, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.|Current address: UMR7622, IBPS, Université Pierre et Marie Curie, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Labouesse
authors.affiliation: Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR 7104, Illkirch, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Georges-Labouesse
mesh_terms: D056704:Adaptive Immunity; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001402:B-Lymphocytes; D001485:Basement Membrane / Q000503:physiopathology; D020170:Caspase 1 / Q000378:metabolism; D003092:Colitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D022002:Hemidesmosomes / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics; D039503:Integrin alpha6 / Q000235:genetics*; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D053538:Keratin-18 / Q000378:metabolism; D053533:Keratin-8 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D009093:Mucus / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010539:Permeability; D012720:Severity of Illness Index; D015398:Signal Transduction; D013601:T-Lymphocytes
chemical_list: D016207:Cytokines; D039503:Integrin alpha6; D039161:Integrin alpha6beta4; D053538:Keratin-18; D053533:Keratin-8; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D020170:Caspase 1
keywords: CELL MATRIX INTERACTION; COLORECTAL CANCER; IBD; INTEGRINS; INTESTINAL BARRIER FUNCTION