title: Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth.
abstract: Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lévy
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France [3] Department of Medical Oncology, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France [4] Pharmacogenomics Unit, Department of Genetics, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Wulfran
authors.initials: W
authors.lastname: Cacheux
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Medhi Ait
authors.initials: MA
authors.lastname: Bara
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: L'Hermitte
authors.affiliation: 1] Institut National de la Recherche Agronomique, Micalis UMR1319, Jouy-en-Josas 78352, France [2] AgroParisTech, Micalis UMR1319, 78350 Jouy-en-Josas, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lepage
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Fraudeau
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Trentesaux
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lemarchand
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Durand
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France [3] Université Paris Diderot, UFR Sciences du Vivant, Sorbonne Paris Cité, Paris 75013, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Crain
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Marchiol
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Renault
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Dumont
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Letourneur
authors.affiliation: 1] Université Lille Nord de France, Lille 59000, France [2] Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille 59800, France [3] Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Lille 59046, France [4] Institut National de la Santé et de la Recherche Médicale, Lille 59045, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Delacre
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France [3] Service d'Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Cochin, Université Paris Descartes, Paris 75014, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Perret
authors.affiliation: 1] Université Lille Nord de France, Lille 59000, France [2] Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille 59800, France [3] Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Lille 59046, France [4] Institut National de la Santé et de la Recherche Médicale, Lille 59045, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France [3] Université Paris Diderot, UFR Sciences du Vivant, Sorbonne Paris Cité, Paris 75013, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Couty
authors.affiliation: 1] Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris 75014, France [2] Institut National de la Sante et de la Recherche Médicale (INSERM), U1016, Paris 75014, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Romagnolo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D000236:Adenoma / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D064806:Dysbiosis; D004789:Enzyme Activation; D005260:Female; D017491:Genes, APC; D054884:Host-Pathogen Interactions; D006801:Humans; D018928:Immunity, Mucosal; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology*; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism*
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; D055372:AMP-Activated Protein Kinases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes