Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth

Jonathan Lévy; Wulfran Cacheux; Medhi Ait Bara; Antoine L'Hermitte; Patricia Lepage; Marie Fraudeau; Coralie Trentesaux; Julie Lemarchand; Aurélie Durand; Anne-Marie Crain; Carmen Marchiol; Gilles Renault; Florent Dumont; Franck Letourneur; Myriam Delacre; Alain Schmitt; Benoit Terris; Christine Perret; Mathias Chamaillard; Jean-Pierre Couty; Béatrice Romagnolo

doi:10.1038/ncb3206

Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth

Nat Cell Biol. 2015 Aug;17(8):1062-73. doi: 10.1038/ncb3206. Epub 2015 Jul 27.

Authors

Jonathan Lévy¹, Wulfran Cacheux², Medhi Ait Bara¹, Antoine L'Hermitte¹, Patricia Lepage³, Marie Fraudeau¹, Coralie Trentesaux¹, Julie Lemarchand¹, Aurélie Durand¹, Anne-Marie Crain⁴, Carmen Marchiol¹, Gilles Renault¹, Florent Dumont¹, Franck Letourneur¹, Myriam Delacre⁵, Alain Schmitt¹, Benoit Terris⁶, Christine Perret¹, Mathias Chamaillard⁵, Jean-Pierre Couty⁴, Béatrice Romagnolo¹

Affiliations

¹ 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.
² 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.
³ 1] Institut National de la Recherche Agronomique, Micalis UMR1319, Jouy-en-Josas 78352, France [2] AgroParisTech, Micalis UMR1319, 78350 Jouy-en-Josas, France.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 26214133
DOI: 10.1038/ncb3206

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Adenocarcinoma / genetics
Adenocarcinoma / immunology
Adenocarcinoma / microbiology
Adenocarcinoma / pathology
Adenocarcinoma / prevention & control*
Adenoma / genetics
Adenoma / immunology
Adenoma / microbiology
Adenoma / pathology
Adenoma / prevention & control*
Animals
Autophagy
Autophagy-Related Protein 7
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / microbiology
Cell Cycle Checkpoints
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / immunology
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Colon / immunology
Colon / metabolism*
Colon / microbiology
Colon / pathology
Colorectal Neoplasms / genetics
Colorectal Neoplasms / immunology
Colorectal Neoplasms / microbiology
Colorectal Neoplasms / pathology
Colorectal Neoplasms / prevention & control*
Disease Models, Animal
Dysbiosis
Enzyme Activation
Female
Genes, APC
Host-Pathogen Interactions
Humans
Immunity, Mucosal*
Male
Mice, Inbred C57BL
Mice, Knockout
Microbiota / immunology*
Microtubule-Associated Proteins / deficiency*
Microtubule-Associated Proteins / genetics
Time Factors
Tumor Burden
Tumor Suppressor Protein p53 / metabolism
Ubiquitin-Activating Enzymes / metabolism*

Substances

Atg7 protein, mouse
Microtubule-Associated Proteins
Tumor Suppressor Protein p53
AMP-Activated Protein Kinases
ATG7 protein, human
Autophagy-Related Protein 7
Ubiquitin-Activating Enzymes