Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

Research output: Contribution to journalArticle

Authors

  • Hayley Davis
  • Shazia Irshad
  • Mukesh Bansal
  • Hannah Rafferty
  • Tatjana Boitsova
  • Emma Jaeger
  • Annabelle Lewis
  • Luke Freeman-Mills
  • Francesc Castro Giner
  • Pedro Rodenas-Cuadrado
  • Sreelakshmi Mallappa
  • Susan Clark
  • Huw Thomas
  • Rosemary Jeffery
  • Richard Poulsom
  • Manuel Rodriguez-Justo
  • Marco Novelli
  • Runjan Chetty
  • Andrew Silver
  • Owen James Sansom
  • Florian R Greten
  • Lai Mun Wang
  • James Edward East
  • Ian Tomlinson
  • Simon John Leedham

Colleges, School and Institutes

External organisations

  • Gastrointestinal Stem cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
  • Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.
  • Colorectal Cancer Genetics, Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, 4 Newark Street, Whitechapel, London, E1 2AT, UK.
  • Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
  • Polyposis registry, St Mark's Hospital, Northwick Park, Watford Road, Harrow, HA1 3UJ, UK.
  • Histopathology department, University College London Hospital, Rockefeller Building, University Street, London, WC1, UK.
  • Laboratory Medicine Program, University Health Network and University of Toronto, 200 Elizabeth Street, Toronto, M5G 2C4, Canada.
  • Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK.
  • Georg-Speyer-Haus Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt, Germany.
  • Cellular Pathology, Level 1, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
  • Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
  • Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.

Abstract

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Details

Original languageEnglish
Pages (from-to)62-70
Number of pages9
JournalNature Medicine
Volume21
Issue number1
Publication statusPublished - Jan 2015

Keywords

  • Animals, Carcinogenesis, Cell Proliferation, Colorectal Neoplasms, Epithelial Cells, Gene Expression Regulation, Neoplastic, Humans, Intercellular Signaling Peptides and Proteins, Intestinal Mucosa, Mice, Mutation, Receptors, G-Protein-Coupled, Stem Cell Niche, Journal Article, Research Support, Non-U.S. Gov't