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Hemidesmosome integrity protects the colon against colitis and colorectal cancer
  1. Adèle De Arcangelis1,2,3,4,
  2. Hussein Hamade1,2,3,4,5,
  3. Fabien Alpy2,3,4,6,7,
  4. Sylvain Normand8,
  5. Emilie Bruyère9,
  6. Olivier Lefebvre4,6,10,11,
  7. Agnès Méchine-Neuville6,12,13,
  8. Stéphanie Siebert1,2,3,4,
  9. Véronique Pfister1,2,3,4,
  10. Patricia Lepage14,
  11. Patrice Laquerriere4,15,
  12. Doulaye Dembele1,2,3,4,
  13. Anne Delanoye-Crespin8,
  14. Sophie Rodius1,2,3,4,16,
  15. Sylvie Robine17,18,
  16. Michèle Kedinger4,6,
  17. Isabelle Van Seuningen9,
  18. Patricia Simon-Assmann4,6,10,11,
  19. Mathias Chamaillard8,
  20. Michel Labouesse1,2,3,4,19,
  21. Elisabeth Georges-Labouesse1,2,3,4
  1. 1 Department of Development and Stem Cells, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France
  2. 2 Inserm, U964, Illkirch, France
  3. 3 CNRS, UMR 7104, Illkirch, France
  4. 4 Université de Strasbourg, Strasbourg, France
  5. 5 Current address: F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA
  6. 6 Inserm, U1109, MNT3 Team, Strasbourg, France
  7. 7 Current address: Department of Functional Genomics and Cancer, IGBMC, Illkirch, France
  8. 8 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
  9. 9 Inserm, Université de Lille, CHRU Lille, UMR-S 1172—Jean-Pierre Aubert Research Center, Lille, France
  10. 10 LabEx Medalis, Université de Strasbourg, Strasbourg, France
  11. 11 Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
  12. 12 CHRU Strasbourg, Hôpital de Hautepierre, Service d'anatomo-pathologie, Strasbourg, France
  13. 13 Current address: Département de Pathologie, Institut Bergonie, Bordeaux, France
  14. 14 UMR1319—MICALIS Institute, INRA, AgroParisTech,Université Paris-Saclay, Jouy-en-Josas, France
  15. 15 CNRS, UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France
  16. 16 Current address: NORLUX Neuro-Oncology Laboratory, CRP-Santé, Luxembourg
  17. 17 Institut Curie, Paris, France
  18. 18 CNRS, UMR 144, Paris, France
  19. 19 Current address: UMR7622, IBPS, Université Pierre et Marie Curie, Paris, France
  1. Correspondence to Adèle De Arcangelis, IGBMC, 1 rue Laurent Fries, F-67400 Illkirch, France; adele{at} Michel Labouesse, UMR7622, IBPS, UPMC, 9 quai Saint-Bernard, F-75005 Paris, France; michel.labouesse{at}


Objective 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.

Design We developed new mouse models inducing IEC-specific ablation of α6 integrin either during development (α6ΔIEC) or in adults (α6ΔIEC-TAM).

Results Strikingly, all α6ΔIEC mutant 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.

Conclusions 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.

  • IBD

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