[en] Primary cilia (PC) are important signaling hubs, and we here explored their role in colonic pathology. In the colon, PC are mostly present on fibroblasts, and exposure of mice to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced acute colitis decreases PC numbers. We generated conditional knockout mice with reduced numbers of PC on colonic fibroblasts. These mice show increased susceptibility to CAC, as well as DSS-induced colitis. Secretome and immunohistochemical analyses of DSS-treated mice display an elevated production of the proinflammatory cytokine IL-6 in PC-deficient colons. An inflammatory environment diminishes PC presence in primary fibroblast cultures, which is triggered by IL-6 as identified by RNA-seq analysis together with blocking experiments. These findings suggest an activation loop between IL-6 production and PC loss. An analysis of PC presence on biopsies of patients with ulcerative colitis or colorectal cancer (CRC) reveals decreased numbers of PC on colonic fibroblasts in pathological compared with surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC.
Paul, Conception; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Tang, Ruizhi ; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Longobardi, Ciro ; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France ; Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands ; Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
Lattanzio, Rossano ; Department of Innovative Technologies in Medicine & Dentistry, Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy
Eguether, Thibaut ; Centre de Recherche Saint Antoine, Sorbonne Université, INSERM, APHP, Paris, France
Turali, Hulya; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Bremond, Julie; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Maurizy, Chloé ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale ; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Gabola, Monica; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Poupeau, Sophie; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Turtoi, Andrei ; Tumor Microenvironment and Resistance to Treatment Laboratory, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France
Denicolai, Emilie; Cancer Research Center of Marseille (CRCM), Laboratory of Predictive Oncology, Inserm U1068 - CNRS UMR7258 - University of Aix-Marseille UM105 - Paoli Calmettes Institute (IPC), Label "Ligue contre le cancer", Marseille, France
Cufaro, Maria Concetta ; Department of Innovative Technologies in Medicine & Dentistry, Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy
Svrcek, Magali; Department of Pathology, AP-HP, Hôpital Saint-Antoine, Sorbonne Université, Paris, France
Seksik, Philippe ; Centre de Recherche Saint Antoine, Sorbonne Université, INSERM, APHP, Paris, France
Castronovo, Vincent ; Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
Delvenne, Philippe ; Cancer Research Center of Marseille (CRCM), Laboratory of Predictive Oncology, Inserm U1068 - CNRS UMR7258 - University of Aix-Marseille UM105 - Paoli Calmettes Institute (IPC), Label "Ligue contre le cancer", Marseille, France ; Department of Pathology, University Hospital (CHU), University of Liège, Liège, Belgium
de Laurenzi, Vincenzo; Department of Innovative Technologies in Medicine & Dentistry, Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy
Da Costa, Quentin ; Cancer Research Center of Marseille (CRCM), Laboratory of Predictive Oncology, Inserm U1068 - CNRS UMR7258 - University of Aix-Marseille UM105 - Paoli Calmettes Institute (IPC), Label "Ligue contre le cancer", Marseille, France
Bertucci, François ; Cancer Research Center of Marseille (CRCM), Laboratory of Predictive Oncology, Inserm U1068 - CNRS UMR7258 - University of Aix-Marseille UM105 - Paoli Calmettes Institute (IPC), Label "Ligue contre le cancer", Marseille, France
Lemmers, Bénédicte ; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Pieragostino, Damiana; Department of Innovative Technologies in Medicine & Dentistry, Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, Chieti, Italy
Mamessier, Emilie ; Cancer Research Center of Marseille (CRCM), Laboratory of Predictive Oncology, Inserm U1068 - CNRS UMR7258 - University of Aix-Marseille UM105 - Paoli Calmettes Institute (IPC), Label "Ligue contre le cancer", Marseille, France
Janke, Carsten ; Institut Curie, Paris Sciences et Lettres (PSL) Research University, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 3348, Label "Equipe FRM", Orsay, France ; Université Paris Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France
Pinet, Valérie ; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
Hahne, Michael ; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
ANR - Agence Nationale de la Recherche INSERM - Institut National de la Santé et de la Recherche Médicale
Funding text :
We are grateful to the excellent platforms in Montpellier, i.e., Montpellier Ressources Imagerie platform, the histology and animal experimentation platforms RHEM and RAM, as well as the IGMM mouse facility ZEFI. Many thanks to Thierry Gostan and the platform SERANAD for help with the statistical analysis. This work was supported by INCA (project 2014‐215, to MH, CJ), Plan Cancer et Cancer Inserm‐ITMO Aviesan 2021 (to MH, CJ, EM), ANR (AAPG2021, CILCOL to MH, CJ, EM), and by the SFNGE (Grant FARE) to MS and TE. The authors are thankful to Professor Kollias BSRC Fleming Greece, for providing the Col6‐Cre mice, Professors Goldstein and Yoder for making available / and / strains, respectively, and to Dr. Stephanie Gofflot, Biobank CHU Liege for providing clinical information. Computing resources for the RNA‐seq primary analysis were provided by the computing facilities DISC (Datacenter IT and Scientific Computing) of the Centre de Recherche en Cancérologie de Marseille. Kif3aflx flx IFT88flx flxWe are grateful to the excellent platforms in Montpellier, i.e., Montpellier Ressources Imagerie platform, the histology and animal experimentation platforms RHEM and RAM, as well as the IGMM mouse facility ZEFI. Many thanks to Thierry Gostan and the platform SERANAD for help with the statistical analysis. This work was supported by INCA (project 2014-215, to MH, CJ), Plan Cancer et Cancer Inserm-ITMO Aviesan 2021 (to MH, CJ, EM), ANR (AAPG2021, CILCOL to MH, CJ, EM), and by the SFNGE (Grant FARE) to MS and TE. The authors are thankful to Professor Kollias BSRC Fleming Greece, for providing the Col6-Cre mice, Professors Goldstein and Yoder for making available Kif3aflx/flx and IFT88flx/flx strains, respectively, and to Dr. Stephanie Gofflot, Biobank CHU Liege for providing clinical information. Computing resources for the RNA-seq primary analysis were provided by the computing facilities DISC (Datacenter IT and Scientific Computing) of the Centre de Recherche en Cancérologie de Marseille.
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