TY - JOUR
T1 - Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis
AU - S:CORT Consortium
AU - Leach, Joshua D G
AU - Vlahov, Nikola
AU - Tsantoulis, Petros
AU - Ridgway, Rachel A
AU - Flanagan, Dustin J
AU - Gilroy, Kathryn
AU - Sphyris, Nathalie
AU - Vázquez, Ester G
AU - Vincent, David F
AU - Faller, William J
AU - Hodder, Michael C
AU - Raven, Alexander
AU - Fey, Sigrid
AU - Najumudeen, Arafath K
AU - Strathdee, Douglas
AU - Nixon, Colin
AU - Hughes, Mark
AU - Clark, William
AU - Shaw, Robin
AU - van Hooff, Sander R
AU - Huels, David J
AU - Medema, Jan Paul
AU - Barry, Simon T
AU - Frame, Margaret C
AU - Unciti-Broceta, Asier
AU - Leedham, Simon J
AU - Inman, Gareth J
AU - Jackstadt, Rene
AU - Thompson, Barry J
AU - Campbell, Andrew D
AU - Tejpar, Sabine
AU - Sansom, Owen J
AU - Beggs, Andrew
PY - 2021/12
Y1 - 2021/12
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 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing/metabolism
KW - Animals
KW - Carcinogenesis/metabolism
KW - Cell Differentiation
KW - Cell Survival
KW - Colon/pathology
KW - Colonic Neoplasms/genetics
KW - Epithelial Cells/metabolism
KW - Fetus/pathology
KW - Inflammation/pathology
KW - Kaplan-Meier Estimate
KW - MAP Kinase Signaling System
KW - Mice, Inbred C57BL
KW - Mutation
KW - Prognosis
KW - Proto-Oncogene Proteins B-raf/genetics
KW - Receptor, Transforming Growth Factor-beta Type I/metabolism
KW - Receptors, Transforming Growth Factor beta/metabolism
KW - Signal Transduction
KW - Spheroids, Cellular/metabolism
KW - Transcription Factors/metabolism
KW - Transforming Growth Factor beta/metabolism
KW - Wnt Proteins/metabolism
KW - Wnt Signaling Pathway
UR - http://www.scopus.com/inward/record.url?scp=85107830538&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-23717-5
DO - 10.1038/s41467-021-23717-5
M3 - Article
C2 - 34103493
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3464
ER -
