Abstract
Gremlin1 (GREM1) is a secreted glycoprotein member of the differential screening-selected gene in aberrant neuroblastoma (DAN) family of bone morphogenetic protein (BMP) antagonists, which binds to BMPs preventing their receptor engagement. Previous studies have identified that stage II colorectal cancer (CRC) patients with high levels of GREM1 gene expression in their tumour tissue have a poorer prognosis. Using a series of in silico and in situ methodologies, we demonstrate that GREM1 gene expression is significantly higher (p < 0.0001) in CRC consensus molecular subtype 4 (CMS4), compared to the other CMS subtypes and correlates (p < 0.0001) with levels of cancer-associated fibroblasts (CAFs) within the CRC tumour microenvironment (TME). Our optimised immunohistochemistry protocol identified endogenous GREM1 protein expression in both the muscularis mucosa and adjacent colonic crypt bases in mouse intestine, in contrast to RNA expression which was shown to localise specifically to the muscularis mucosa, as determined by in situ hybridisation. Importantly, we demonstrate that cells with high levels of GREM1 expression display low levels of phospho-Smad1/5, consistent with reduced BMP signalling. Taken together, these data highlight a novel paracrine signalling circuit, which involves uptake of mature GREM1 protein by colonic crypt cells following secretion from neighbouring fibroblasts in the TME.
Original language | English |
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Pages (from-to) | 4630-4639 |
Number of pages | 10 |
Journal | Oncotarget |
Volume | 10 |
Issue number | 45 |
DOIs | |
Publication status | Published - 23 Jul 2019 |
Keywords
- Colorectal cancer
- Fibroblasts
- Gremlin1
- Pathology
- Stroma
ASJC Scopus subject areas
- Oncology
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Dive into the research topics of 'Fibroblast-derived Gremlin1 localises to epithelial cells at the base of the intestinal crypt'. Together they form a unique fingerprint.Student theses
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Defining the clinical importance of epithelial-stroma-immune signalling in colorectal cancer using a molecular pathology approach
McCorry, A. (Author), Lawler, M. (Supervisor), Dunne, P. (Supervisor) & Salto-Tellez, M. (Supervisor), Jul 2021Student thesis: Doctoral Thesis › Doctor of Philosophy
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Elucidating the role of Gremlin1 in colorectal cancer
Dutton, L. (Author), Brazil, D. (Supervisor), Dunne, P. (Supervisor) & Lawler, M. (Supervisor), Dec 2020Student thesis: Doctoral Thesis › Doctor of Philosophy
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Interpreting transcriptional signatures and their relevance to disease biology, prognosis and treatment resistance in colorectal cancer
Hoare, O. (Author), Lawler, M. (Supervisor), Dunne, P. (Supervisor) & Van Schaeybroeck, S. (Supervisor), Jul 2020Student thesis: Doctoral Thesis › Doctor of Philosophy
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