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

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

Author information

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.

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.

PMID:
26214133
DOI:
10.1038/ncb3206
[Indexed for MEDLINE]

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