Intestinal epithelial Notch-1 protects from colorectal mucinous adenocarcinoma

// David Dunkin 1, 2 , Alina C. Iuga 3 , Sanda Mimouna 4, 5, 6 , Carolyn L. Harris 4, 6, 7 , Jean-Vianney Haure-Mirande 4, 6, 8 , Dominique Bozec 4, 6, 9, 10 , Garabet Yeretssian 4, 6, 10, 11, *, ** and Stephanie Dahan 4, 6, 12, *, ** 1 Department of Pediatric Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 2 The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 3 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA 4 The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 5 Immunology and Autoimmunity Research Department, Hospital for Special Surgery Research Institute, New York, NY 10021, USA 6 Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 7 Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 8 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 9 Brain Tumor Nanotechnology Laboratory, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 10 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 11 The Leona M. and Harry B. Helmsley Charitable Trust, New York, NY 10169, USA 12 Sobi, Inc. Waltham, MA 02452, USA * These authors contributed equally to the work ** The authors changed affiliation after the course of the work. SD is currently employed by Sobi, Inc. but the article in no way represents the work product, views or opinions of Sobi, Inc. GY is currently employed by The Leona M. and Harry B. Helmsley Charitable Trust, but the article in no way represents the work, views or opinions of Helmsley Correspondence to: David Dunkin, email: David.dunkin@mssm.edu Keywords: Notch-1; mucinous adenocarcinoma; colorectal cancer Abbreviations: Atoh-1 (Atonal homolog-1), CRC (colorectal cancer), RBP-J (Recombinant Binding Protein Suppressor of Hairless), Hes-1 (Hairy and enhancer of split-1), VN -/- (Villin-Cre/Notch-1 fl/f ) Received: February 28, 2018      Accepted: August 23, 2018      Published: September 11, 2018 ABSTRACT Increasing evidence links Notch-1 signaling with the maintenance of intestinal architecture and homeostasis. Dysfunction in the common Notch-1 pathway transcription factor recombinant binding protein suppressor of hairless (RBP-J) is associated with loss of epithelial barrier integrity and aberrant conversion of proliferative crypt cells into goblet cells. Furthermore, we have recently discovered that epithelial Notch-1 is indispensable in bridging innate and adaptive immunity in the gut and is required for supporting protective epithelial pro-inflammatory responses. Yet, the epithelial specific function of Notch-1 in intestinal tumorigenesis remains unknown. We generated Villin-Cre/Notch-1 fl/fl ( VN -/- ) mice that are selectively deficient in Notch-1 in intestinal epithelial cells. Intestinal epithelial Notch-1 preserved barrier function and integrity, whereas lack of epithelial Notch-1 induced goblet cell hyperplasia, spontaneous serrated lesions, multifocal low- and high-grade dysplasia and colonic mucinous neoplasms in mice. Over time, VN -/- mice displayed high occurrence of colorectal mucinous adenocarcinomas, which correlated with increased levels of mitogenic, angiogenic and pro-tumorigenic gene expression. Finally, we found that the expression of Notch-1 is significantly reduced in human colorectal mucinous adenocarcinoma when compared to colorectal adenocarcinoma. Taken together, our findings reveal a novel and critical protective role for Notch-1 in controlling intestinal tumorigenesis.