TY  - JOUR
A1  - Leach, JDG
A1  - Vlahov, N
A1  - Tsantoulis, P
A1  - Ridgway, RA
A1  - Flanagan, DJ
A1  - Gilroy, K
A1  - Sphyris, N
A1  - Vázquez, EG
A1  - Vincent, DF
A1  - Faller, WJ
A1  - Hodder, MC
A1  - Raven, A
A1  - Fey, S
A1  - Najumudeen, AK
A1  - Strathdee, D
A1  - Nixon, C
A1  - Hughes, M
A1  - Clark, W
A1  - Shaw, R
A1  - S:CORT consortium
A1  - van Hooff, SR
A1  - Huels, DJ
A1  - Medema, JP
A1  - Barry, ST
A1  - Frame, MC
A1  - Unciti-Broceta, A
A1  - Leedham, SJ
A1  - Inman, GJ
A1  - Jackstadt, R
A1  - Thompson, BJ
A1  - Campbell, AD
A1  - Tejpar, S
A1  - Sansom, OJ
KW  - Adaptor Proteins
KW  -  Signal Transducing
KW  -  Animals
KW  -  Carcinogenesis
KW  -  Cell Differentiation
KW  -  Cell Survival
KW  -  Colon
KW  -  Colonic Neoplasms
KW  -  Epithelial Cells
KW  -  Fetus
KW  -  Inflammation
KW  -  Kaplan-Meier Estimate
KW  -  MAP Kinase Signaling System
KW  -  Mice
KW  -  Inbred C57BL
KW  -  Mutation
KW  -  Prognosis
KW  -  Proto-Oncogene Proteins B-raf
KW  -  Receptor
KW  -  Transforming Growth Factor-beta Type I
KW  -  Receptors
KW  -  Transforming Growth Factor beta
KW  -  Signal Transduction
KW  -  Spheroids
KW  -  Cellular
KW  -  Transcription Factors
KW  -  Transforming Growth Factor beta
KW  -  Wnt Proteins
KW  -  Wnt Signaling Pathway
JF  - Nature Communications
UR  - https://doi.org/10.1038/s41467-021-23717-5
N2  - 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 TGF? signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGF?-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 TGF?-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.
ID  - discovery10130448
N1  - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article?s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article?s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
AV  - public
Y1  - 2021/06/08/
VL  - 12
TI  - Oncogenic BRAF, unrestrained by TGF?-receptor signalling, drives right-sided colonic tumorigenesis.
ER  -