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

Hayley Davis; Shazia Irshad; Mukesh Bansal; Hannah Rafferty; Tatjana Boitsova; Chiara Bardella; 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

doi:10.1038/nm.3750

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

Hayley Davis, Shazia Irshad, Mukesh Bansal, Hannah Rafferty, Tatjana Boitsova, Chiara Bardella, 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 SilverOwen James Sansom, Florian R Greten, Lai Mun Wang, James Edward East, Ian Tomlinson, Simon John Leedham

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

139 Citations (Scopus)

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.

Original language	English
Pages (from-to)	62-70
Number of pages	9
Journal	Nature Medicine
Volume	21
Issue number	1
Early online date	1 Dec 2014
DOIs	https://doi.org/10.1038/nm.3750
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Davis, H., Irshad, S., Bansal, M., Rafferty, H., Boitsova, T., Bardella, C., Jaeger, E., Lewis, A., Freeman-Mills, L., Giner, F. C., Rodenas-Cuadrado, P., Mallappa, S., Clark, S., Thomas, H., Jeffery, R., Poulsom, R., Rodriguez-Justo, M., Novelli, M., Chetty, R., ... Leedham, S. J. (2015). Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nature Medicine, 21(1), 62-70. https://doi.org/10.1038/nm.3750

@article{5acdd50e686146e8bdefe893886c913e,

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.",

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",

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

year = "2015",

month = jan,

doi = "10.1038/nm.3750",

language = "English",

volume = "21",

pages = "62--70",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "1",

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Davis, H, Irshad, S, Bansal, M, Rafferty, H, Boitsova, T, Bardella, C, Jaeger, E, Lewis, A, Freeman-Mills, L, Giner, FC, Rodenas-Cuadrado, P, Mallappa, S, Clark, S, Thomas, H, Jeffery, R, Poulsom, R, Rodriguez-Justo, M, Novelli, M, Chetty, R, Silver, A, Sansom, OJ, Greten, FR, Wang, LM, East, JE, Tomlinson, I & Leedham, SJ 2015, 'Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche', Nature Medicine, vol. 21, no. 1, pp. 62-70. https://doi.org/10.1038/nm.3750

TY - JOUR

T1 - Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

AU - Davis, Hayley

AU - Irshad, Shazia

AU - Bansal, Mukesh

AU - Rafferty, Hannah

AU - Boitsova, Tatjana

AU - Bardella, Chiara

AU - Jaeger, Emma

AU - Lewis, Annabelle

AU - Freeman-Mills, Luke

AU - Giner, Francesc Castro

AU - Rodenas-Cuadrado, Pedro

AU - Mallappa, Sreelakshmi

AU - Clark, Susan

AU - Thomas, Huw

AU - Jeffery, Rosemary

AU - Poulsom, Richard

AU - Rodriguez-Justo, Manuel

AU - Novelli, Marco

AU - Chetty, Runjan

AU - Silver, Andrew

AU - Sansom, Owen James

AU - Greten, Florian R

AU - Wang, Lai Mun

AU - East, James Edward

AU - Tomlinson, Ian

AU - Leedham, Simon John

PY - 2015/1

Y1 - 2015/1

N2 - 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.

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.

KW - Animals

KW - Carcinogenesis

KW - Cell Proliferation

KW - Colorectal Neoplasms

KW - Epithelial Cells

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Intercellular Signaling Peptides and Proteins

KW - Intestinal Mucosa

KW - Mice

KW - Mutation

KW - Receptors, G-Protein-Coupled

KW - Stem Cell Niche

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nm.3750

DO - 10.1038/nm.3750

M3 - Article

C2 - 25419707

SN - 1078-8956

VL - 21

SP - 62

EP - 70

JO - Nature Medicine

JF - Nature Medicine

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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