التفاصيل البيبلوغرافية
| العنوان: |
Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. |
| المؤلفون: |
Leach, Joshua D. G., Vlahov, Nikola, Tsantoulis, Petros, Ridgway, Rachel A., Flanagan, Dustin J., Gilroy, Kathryn, Sphyris, Nathalie, Vázquez, Ester G., Vincent, David F., Faller, William J., Hodder, Michael C., Raven, Alexander, Fey, Sigrid, Najumudeen, Arafath K., Strathdee, Douglas, Nixon, Colin, Hughes, Mark, Clark, William, Shaw, Robin, S:CORT consortium |
| المصدر: |
Nature Communications; 6/8/2021, Vol. 12 Issue 1, p1-15, 15p |
| مصطلحات موضوعية: |
BRAF genes, COLORECTAL cancer, LABORATORY mice, PROGNOSIS, PHENOTYPES |
| مستخلص: |
Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells. Right-sided colorectal cancer (rCRC) has a different mutational spectrum to the left-sided counterpart. Here the authors develop a mouse model of rCRC that recapitulates human BRAF-mutant rCRC and show that loss of TGFβ-receptor signalling and inflammation induce the development of colonic tumours with a foetal-like phenotype. [ABSTRACT FROM AUTHOR] |
|
Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder