title: Epithelial calcineurin controls microbiota-dependent intestinal tumor development.
abstract: Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell-intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.|Center for Regenerative Therapies, Technical University Dresden, Dresden, Germany.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Peuker
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Muff
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön, Germany.|Institute for Experimental Medicine, Christian-Albrechts University of Kiel, Kiel, Germany.
authors.forename: Jun
authors.identifier: 0000-0002-8859-7707
authors.initials: J
authors.lastname: Wang
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön, Germany.|Institute for Experimental Medicine, Christian-Albrechts University of Kiel, Kiel, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Künzel
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Bosse
authors.affiliation: Department of General Pediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.|Department of Pediatrics, University Medical Center Dresden, Technical University Dresden, Dresden, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Zeissig
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.|Center for Regenerative Therapies, Technical University Dresden, Dresden, Germany.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Luzzi
authors.affiliation: Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany.
authors.forename: Marijana
authors.initials: M
authors.lastname: Basic
authors.affiliation: Center for Regenerative Therapies, Technical University Dresden, Dresden, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Strigli
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ulbricht
authors.affiliation: Division of Gastroenterology, Addenbrooke Hospital, University of Cambridge, Cambridge, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Kaser
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.affiliation: Department of Clinical Pathobiochemistry, Faculty of Medicine, Technical University Dresden, Dresden, Germany.|Institute of Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technical University Dresden, Dresden, Germany.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands.|Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
authors.affiliation: Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.affiliation: Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Egberts
authors.affiliation: Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.affiliation: San Raffaele University and Scientific Institute, Milan, Italy.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Bleich
authors.affiliation: Institute of Pathology, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.|Department of Medicine I, University Medical Center Dresden, Technical University Dresden, Dresden, Germany.
authors.forename: Jochen
authors.identifier: 0000-0002-2421-6127
authors.initials: J
authors.lastname: Hampe
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Max Planck Institute for Evolutionary Biology, Plön, Germany.|Institute for Experimental Medicine, Christian-Albrechts University of Kiel, Kiel, Germany.
authors.forename: John F
authors.initials: JF
authors.lastname: Baines
authors.affiliation: Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany.|Center for Regenerative Therapies, Technical University Dresden, Dresden, Germany.|Department of Medicine I, University Medical Center Dresden, Technical University Dresden, Dresden, Germany.|Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeissig
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000382:microbiology / Q000401:mortality; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000378:metabolism*; D000069467:Fecal Microbiota Transplantation; D005434:Flow Cytometry; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000502:physiology*; D017491:Genes, APC; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000382:microbiology; D007422:Intestines / Q000382:microbiology; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D014411:Neoplastic Stem Cells; D009940:Organoids; D011379:Prognosis; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis
chemical_list: D050778:NFATC Transcription Factors; D012336:RNA, Ribosomal, 16S; D019703:Calcineurin