title: Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche.
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.
authors.affiliation: Gastrointestinal Stem cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Davis
authors.affiliation: Gastrointestinal Stem cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Shazia
authors.initials: S
authors.lastname: Irshad
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Gastrointestinal Stem cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Rafferty
authors.affiliation: Gastrointestinal Stem cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.|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.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Boitsova
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bardella
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Jaeger
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lewis
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Freeman-Mills
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Francesc Castro
authors.initials: FC
authors.lastname: Giner
authors.affiliation: Gastrointestinal Stem cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Pedro
authors.initials: P
authors.lastname: Rodenas-Cuadrado
authors.affiliation: Polyposis registry, St Mark's Hospital, Northwick Park, Watford Road, Harrow, HA1 3UJ, UK.
authors.forename: Sreelakshmi
authors.initials: S
authors.lastname: Mallappa
authors.affiliation: Polyposis registry, St Mark's Hospital, Northwick Park, Watford Road, Harrow, HA1 3UJ, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Clark
authors.affiliation: Polyposis registry, St Mark's Hospital, Northwick Park, Watford Road, Harrow, HA1 3UJ, UK.
authors.forename: Huw
authors.initials: H
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Jeffery
authors.affiliation: 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.
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.affiliation: Histopathology department, University College London Hospital, Rockefeller Building, University Street, London, WC1, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.affiliation: Histopathology department, University College London Hospital, Rockefeller Building, University Street, London, WC1, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.affiliation: Laboratory Medicine Program, University Health Network and University of Toronto, 200 Elizabeth Street, Toronto, M5G 2C4, Canada.
authors.forename: Runjan
authors.initials: R
authors.lastname: Chetty
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.affiliation: Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK.
authors.forename: Owen James
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Georg-Speyer-Haus Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt, Germany.
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.affiliation: Cellular Pathology, Level 1, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
authors.forename: Lai Mun
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
authors.forename: James Edward
authors.initials: JE
authors.lastname: East
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.|Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: Gastrointestinal Stem cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.|Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
authors.forename: Simon John
authors.initials: SJ
authors.lastname: Leedham
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D055153:Stem Cell Niche / Q000235:genetics*
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled