Imperial College London
Professor Sir Huw Thomas

Professor Sir Huw Thomas

Faculty of Medicine, Department of Surgery & Cancer

Emeritus Professor
 
 
 
//

Contact

 

+44 (0)20 8235 4266huw.thomas

 
 
//

Location

 

St Marks HospitalNorthwick Park and St Marks Site

//

Summary

 

Publications

Citation

BibTex format

@article{Davis:2015:10.1038/nm.3750,
author = {Davis, H and Irshad, S and Bansal, M and Rafferty, H and Boitsova, T and Bardella, C and Jaeger, E and Lewis, A and Freeman-Mills, L and Giner, FC and Rodenas-Cuadrado, P and Mallappa, S and Clark, S and Thomas, H and Jeffery, R and Poulsom, R and Rodriguez-Justo, M and Novelli, M and Chetty, R and Silver, A and Sansom, OJ and Greten, FR and Wang, LM and East, JE and Tomlinson, I and Leedham, SJ},
doi = {10.1038/nm.3750},
journal = {Nature Medicine},
pages = {62--70},
title = {Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche},
url = {http://dx.doi.org/10.1038/nm.3750},
volume = {21},
year = {2015}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Davis,H
AU  - Irshad,S
AU  - Bansal,M
AU  - Rafferty,H
AU  - Boitsova,T
AU  - Bardella,C
AU  - Jaeger,E
AU  - Lewis,A
AU  - Freeman-Mills,L
AU  - Giner,FC
AU  - Rodenas-Cuadrado,P
AU  - Mallappa,S
AU  - Clark,S
AU  - Thomas,H
AU  - Jeffery,R
AU  - Poulsom,R
AU  - Rodriguez-Justo,M
AU  - Novelli,M
AU  - Chetty,R
AU  - Silver,A
AU  - Sansom,OJ
AU  - Greten,FR
AU  - Wang,LM
AU  - East,JE
AU  - Tomlinson,I
AU  - Leedham,SJ
DO  - 10.1038/nm.3750
EP  - 70
PY  - 2015///
SN  - 1546-170X
SP  - 62
TI  - Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche
T2  - Nature Medicine
UR  - http://dx.doi.org/10.1038/nm.3750
UR  - http://www.ncbi.nlm.nih.gov/pubmed/25419707
UR  - http://hdl.handle.net/10044/1/39587
VL  - 21
ER  -
Download