Cancer Induces a Stress Ileopathy Depending on beta-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis
Yonekura, Satoru; Terrisse, Safae; Silva, Carolina Alves Costa; Lafarge, Antoine; Iebba, Valerio; Ferrere, Gladys; Goubet, Anne Gaëlle; Fahrner, Jean Eudes; Lahmar, Imran; Ueda, Kousuke; Mansouri, Gibrail; Pizzato, Eugénie; Ly, Pierre; Mazzenga, Marine; Thelemaque, Cassandra; Fidelle, Marine; Jaulin, Fanny; Cartry, Jérôme; Deloger, Marc; Aglave, Marine; Droin, Nathalie; Opolon, Paule; Puget, Angélique; Mann, Fanny; Neunlist, Michel; Bessard, Anne; Aymeric, Laetitia; Matysiak-Budnik, Tamara; Bosq, Jacques; Hofman, Paul; Duong, Connie P.M.; Ugolini, Sophie; Quiniou, Valentin; Berrard, Sylvie; Ryffel, Bernhard; Kepp, Oliver; Kroemer, Guido; Routy, Bertrand; Lordello, Leonardo; Bani, Mohamed Amine; Segata, Nicola; Yengej, Fjodor Yousef; Clevers, Hans; Scoazec, Jean Yves; Pasolli, Edoardo; Derosa, Lisa; Zitvogel, Laurence
(2022) Cancer Discovery, volume 12, issue 4, pp. 1128 - 1151
(Article)
Abstract
Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over
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cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free lit-termates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies. SIGNIFICANCE: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor–dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.–related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy.
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Keywords: Oncology
ISSN: 2159-8274
Publisher: American Association for Cancer Research Inc.
Note: Funding Information: L. Zitvogel and G. Kroemer are supported by the Seerave Foundation, Gustave Roussy Odyssea, the Gustave Roussy Foundation, the European Union Horizon 2020 Project Oncobiome (Project Number: 825410); the RHU LUMIERE: ANR-16-RHUS-0008; the Ligue contre le Cancer (équipe labellisée); Agence Nationale de la Recherche (ANR)—Projets blancs; ANR ILEOBIOME, 19-CE15-0029-01, ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; AMMICa US23/CNRS UMS3655; Association pour la Recherche sur le Cancer (ARC); Association “Le Cancer du Sein, Parlons-en!”; Cancéropôle Ile-de-France; Chancelerie des Universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). This work is supported by the Prism project funded by the Agence Nationale de la Recherche under grant number ANR-18-IBHU-0002. F. Mann is supported by INCa, la Ligue contre le cancer, and Fondation ARC (PAIR PANCREAS 186738). S. Terrisse is financially supported by INSERM-PLAN CANCER. S. Yonekura, B. Routy, and L. Derosa were funded by Gustave Roussy Course of Excellence in Oncology–Fondation Philanthropia. O. Kepp is supported by the DIM ELICIT initiative of the Ile de France. Funding Information: L. Zitvogel and G. Kroemer are supported by the Seerave Foun-dation, Gustave Roussy Odyssea, the Gustave Roussy Foundation, the European Union Horizon 2020 Project Oncobiome (Project Number: 825410); the RHU LUMIERE: ANR-16-RHUS-0008; the Ligue contre le Cancer (équipe labellisée); Agence Nationale de la Recherche (ANR)—Projets blancs; ANR ILEOBIOME, 19-CE15-0029-01, ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; AMMICa US23/CNRS UMS3655; Association pour la Recherche sur le Cancer (ARC); Association “Le Cancer du Sein, Parlons-en!”; Cancéropôle Ile-de-France; Chancelerie des Universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Research Area Network on Cardiovas-cular Diseases (ERA-CVD, MINOTAUR); Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085), Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). This work is supported by the Prism project funded by the Agence Nationale de la Recherche under grant number ANR-18-IBHU-0002. F. Mann is supported by INCa, la Ligue contre le cancer, and Fondation ARC (PAIR PANCREAS 186738). S. Terrisse is financially supported by INSERM-PLAN CANCER. S. Yonekura, B. Routy, and L. Derosa were funded by Gustave Roussy Course of Excellence in Oncology–Fondation Philanthropia. O. Kepp is supported by the DIM ELICIT initiative of the Ile de France. Funding Information: J. Fahrner reports other support from Transgene outside the submitted work. O. Kepp is a cofounder of Samsara Therapeutics. G. Kroemer reports grants from Eleor, Kaleido, Lytix Pharma, Pharma-Mar, Samsara Therapeutics, Sanofi, Sotio, Vascage, and Vasculox/ Tioma and other support from EverImmune outside the submitted work; is on the board of directors for the Bristol Myers Squibb Foundation France; and is a scientific cofounder of EverImmune, Samsara Therapeutics, and Therafast Bio. N. Segata reports grants from Onco-biome during the conduct of the study. H. Clevers reports personal fees from Roche outside the submitted work and is an inventor on a Publisher Copyright: ©2021 American Association for Cancer Research.
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