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

• Published in: Nature cell biology Vol. 17; no. 8; pp. 1062 - 1073
• Main Authors: Lévy, Jonathan, Cacheux, Wulfran, Bara, Medhi Ait, L’Hermitte, Antoine, Lepage, Patricia, Fraudeau, Marie, Trentesaux, Coralie, Lemarchand, Julie, Durand, Aurélie, Crain, Anne-Marie, Marchiol, Carmen, Renault, Gilles, Dumont, Florent, Letourneur, Franck, Delacre, Myriam, Schmitt, Alain, Terris, Benoit, Perret, Christine, Chamaillard, Mathias, Couty, Jean-Pierre, Romagnolo, Béatrice
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2015; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/2; 13/21; 13/31; 13/51; 14/28; 38/23; 38/32; 38/39; 38/61; 631/67; 631/80/39; 64/60; Adenocarcinoma - genetics; Adenocarcinoma - immunology; Adenocarcinoma - microbiology; Adenocarcinoma - pathology; Adenocarcinoma - prevention & control; Adenoma - genetics; Adenoma - immunology; Adenoma - microbiology; Adenoma - pathology; Adenoma - prevention & control; AMP-Activated Protein Kinases - metabolism; Animals; Autophagy; Autophagy (Cytology); Autophagy-Related Protein 7; Cancer Research; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - microbiology; Cell Biology; Cell Cycle Checkpoints; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - immunology; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cellular proteins; Colon - immunology; Colon - metabolism; Colon - microbiology; Colon - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - microbiology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - prevention & control; Development and progression; Developmental Biology; Disease Models, Animal; Dysbiosis; Enzyme Activation; Female; Gene expression; Genes, APC; Genetic aspects; Health aspects; Host-Pathogen Interactions; Humans; Immune response; Immunity, Mucosal; Inactivation; Life Sciences; Male; Mice, Inbred C57BL; Mice, Knockout; Microbiota - immunology; Microtubule-Associated Proteins - deficiency; Microtubule-Associated Proteins - genetics; Properties; Stem Cells; Time Factors; Tumor Burden; Tumor Suppressor Protein p53 - metabolism; Tumors; Ubiquitin-Activating Enzymes - metabolism
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3206

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.
Romagnolo and colleagues report that
Atg7
deficiency has a tumour-suppressive role in the intestinal epithelium, by inducing a microbiome-influenced immune response and inhibiting tumour growth through p53- and AMPK-related mechanisms.