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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche
Nature Medicine, Volume 21, No. 1, Year 2015
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Description
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. © 2014 Nature America, Inc. All rights reserved.
Authors & Co-Authors
Bansal, Mukesh
United States, New York
Columbia University Irving Medical Center
Jaeger, Emma E.M.
United Kingdom, Oxford
University of Oxford
Mallappa, Sreelakshmi
United Kingdom, Harrow
St Mark’s Hospital
Clark, Susan K.
United Kingdom, Harrow
St Mark’s Hospital
Thomas, Huw J.W.
United Kingdom, Harrow
St Mark’s Hospital
Poulsom, Richard
United Kingdom, London
Barts and the London School of Medicine and Dentistry
Rodríguez-Justo, Manuel
United Kingdom, London
University College London Hospitals Nhs Foundation Trust
Novelli, Marco
United Kingdom, London
University College London Hospitals Nhs Foundation Trust
Chetty, Runjan M.
Canada, Toronto
University of Toronto
Silver, Andrew R.J.
United Kingdom, London
Barts and the London School of Medicine and Dentistry
Greten, Florian R.
Germany, Frankfurt am Main
Georg-speyer-haus
Wang, Laimun
United Kingdom, Oxford
John Radcliffe Hospital
East, James Edward
United Kingdom, Oxford
Nuffield Department of Medicine
Tomlinson, Ian P.M.
United Kingdom, Oxford
University of Oxford
United Kingdom, Royston
National Institute for Health and Care Research
Leedham, Simon John
United Kingdom, Oxford
University of Oxford
United Kingdom, Oxford
Nuffield Department of Medicine
Statistics
Citations: 179
Authors: 15
Affiliations: 11
Identifiers
Doi:
10.1038/nm.3750
ISSN:
10788956
Research Areas
Cancer
Genetics And Genomics