Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Joshua D.G. Leach; Nikola Vlahov; Petros Tsantoulis; Rachel A. Ridgway; Dustin J. Flanagan; Kathryn Gilroy; Nathalie Sphyris; Ester G. Vázquez; David F. Vincent; William J. Faller; Michael C. Hodder; Alexander Raven; Sigrid Fey; Arafath K. Najumudeen; Douglas Strathdee; Colin Nixon; Mark Hughes; William Clark; Robin Shaw; S:CORT consortium; Sander R. van Hooff; David J. Huels; Jan Paul Medema; Simon T. Barry; Margaret C. Frame; Asier Unciti-Broceta; Simon J. Leedham; Gareth J. Inman; Rene Jackstadt; Barry J. Thompson; Andrew D. Campbell; Sabine Tejpar; Owen J. Sansom

doi:10.1038/s41467-021-23717-5

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Joshua D.G. Leach
, Nikola Vlahov
, Petros Tsantoulis
, Rachel A. Ridgway
, Dustin J. Flanagan
, Kathryn Gilroy
, Nathalie Sphyris
, Ester G. Vázquez
, David F. Vincent
, William J. Faller
, Michael C. Hodder
, Alexander Raven
, Sigrid Fey
, Arafath K. Najumudeen
, Douglas Strathdee
, Colin Nixon
, Mark Hughes
, William Clark
, Robin Shaw
, S:CORT consortium

Sander R. van Hooff, David J. Huels, Jan Paul Medema, Simon T. Barry, Margaret C. Frame, Asier Unciti-Broceta, Simon J. Leedham, Gareth J. Inman, Rene Jackstadt, Barry J. Thompson, Andrew D. Campbell, Sabine Tejpar, Owen J. Sansom

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

62 Citations (Scopus)

Abstract

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.

Original language	English
Article number	3464
Number of pages	15
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23717-5
Publication status	Published - 8 Jun 2021
Externally published	Yes

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SDG 3 Good Health and Well-being

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Leach, J. D. G., Vlahov, N., Tsantoulis, P., Ridgway, R. A., Flanagan, D. J., Gilroy, K., Sphyris, N., Vázquez, E. G., Vincent, D. F., Faller, W. J., Hodder, M. C., Raven, A., Fey, S., Najumudeen, A. K., Strathdee, D., Nixon, C., Hughes, M., Clark, W., Shaw, R., ... Sansom, O. J. (2021). Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nature Communications, 12(1), Article 3464. https://doi.org/10.1038/s41467-021-23717-5

@article{2d85888a143b4d99aa0f06bfb63321fb,

title = "Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis",

abstract = "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.",

author = "Leach, \{Joshua D.G.\} and Nikola Vlahov and Petros Tsantoulis and Ridgway, \{Rachel A.\} and Flanagan, \{Dustin J.\} and Kathryn Gilroy and Nathalie Sphyris and V{\'a}zquez, \{Ester G.\} and Vincent, \{David F.\} and Faller, \{William J.\} and Hodder, \{Michael C.\} and Alexander Raven and Sigrid Fey and Najumudeen, \{Arafath K.\} and Douglas Strathdee and Colin Nixon and Mark Hughes and William Clark and Robin Shaw and Tim Maughan and Manuel Salto-Tellez and Philip Quirke and Viktor Koelzer and Philip Dunne and Andrew Beggs and Peter Campbell and Francesca Buffa and Chris Holmes and Rick Kaplan and Louise Brown and Mark Lawler and Joshua Hordern and Ian Tomlinson and Leedham, \{Simon J.\} and Dion Morton and \{S:CORT consortium\} and \{van Hooff\}, \{Sander R.\} and Huels, \{David J.\} and Medema, \{Jan Paul\} and Barry, \{Simon T.\} and Frame, \{Margaret C.\} and Asier Unciti-Broceta and Leedham, \{Simon J.\} and Inman, \{Gareth J.\} and Rene Jackstadt and Thompson, \{Barry J.\} and Campbell, \{Andrew D.\} and Sabine Tejpar and Sansom, \{Owen J.\}",

note = "Funding Information: S.T.B. is an employee of AstraZeneca. O.J.S. receives funding from AstraZeneca and Novartis. All other authors declare no conflicts of interest. Funding Information: The authors thank the staff in the Central Services, the Histology Service, the Molecular Technology and Reagent Services, the Transgenic Technology Laboratory, and the Biological Services Unit at the Cancer Research UK Beatson Institute for their technical expertise and support (Cancer Research UK core grant, A17196). We are also grateful to Catherine Winchester for assistance with editing the manuscript. O.J.S. and his lab members were supported by grants from Cancer Research UK (A21139, A12481, A17196, A29055, C7932/A26825), the European Research Council (Starting Grant, 311301), and Pancreatic Cancer UK (Future Leaders Academy studentship; S.F.). G.J.I. was supported by Cancer Research UK (A29802). The Stratification in Colorectal Cancer (S:CORT) consortium was funded by the Medical Research Council and Cancer Research UK (grant award no MR/M016587/1). S.T. was supported as a 375 Senior Clinical Investigator by the Research Foundation—Flanders (FWO). J.D.G.L. was supported by a Medical Research Council Clinical Research Training Fellowship (MR/N021800/1). R.J. was funded by the Marie Sk{\l}odowska-Curie Actions Individual Fellowship (European Research Council, 659666). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jun,

day = "8",

doi = "10.1038/s41467-021-23717-5",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Leach, JDG, Vlahov, N, Tsantoulis, P, Ridgway, RA, Flanagan, DJ, Gilroy, K, Sphyris, N, Vázquez, EG, Vincent, DF, Faller, WJ, Hodder, MC, Raven, A, Fey, S, Najumudeen, AK, Strathdee, D, Nixon, C, Hughes, M, Clark, W, Shaw, R, S:CORT consortium, van Hooff, SR, Huels, DJ, Medema, JP, Barry, ST, Frame, MC, Unciti-Broceta, A, Leedham, SJ, Inman, GJ, Jackstadt, R, Thompson, BJ, Campbell, AD, Tejpar, S & Sansom, OJ 2021, 'Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis', Nature Communications, vol. 12, no. 1, 3464. https://doi.org/10.1038/s41467-021-23717-5

TY - JOUR

T1 - Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

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 - Maughan, Tim

AU - Salto-Tellez, Manuel

AU - Quirke, Philip

AU - Koelzer, Viktor

AU - Dunne, Philip

AU - Beggs, Andrew

AU - Campbell, Peter

AU - Buffa, Francesca

AU - Holmes, Chris

AU - Kaplan, Rick

AU - Brown, Louise

AU - Lawler, Mark

AU - Hordern, Joshua

AU - Tomlinson, Ian

AU - Leedham, Simon J.

AU - Morton, Dion

AU - S:CORT consortium

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.

N1 - Funding Information: S.T.B. is an employee of AstraZeneca. O.J.S. receives funding from AstraZeneca and Novartis. All other authors declare no conflicts of interest. Funding Information: The authors thank the staff in the Central Services, the Histology Service, the Molecular Technology and Reagent Services, the Transgenic Technology Laboratory, and the Biological Services Unit at the Cancer Research UK Beatson Institute for their technical expertise and support (Cancer Research UK core grant, A17196). We are also grateful to Catherine Winchester for assistance with editing the manuscript. O.J.S. and his lab members were supported by grants from Cancer Research UK (A21139, A12481, A17196, A29055, C7932/A26825), the European Research Council (Starting Grant, 311301), and Pancreatic Cancer UK (Future Leaders Academy studentship; S.F.). G.J.I. was supported by Cancer Research UK (A29802). The Stratification in Colorectal Cancer (S:CORT) consortium was funded by the Medical Research Council and Cancer Research UK (grant award no MR/M016587/1). S.T. was supported as a 375 Senior Clinical Investigator by the Research Foundation—Flanders (FWO). J.D.G.L. was supported by a Medical Research Council Clinical Research Training Fellowship (MR/N021800/1). R.J. was funded by the Marie Skłodowska-Curie Actions Individual Fellowship (European Research Council, 659666). Publisher Copyright: © 2021, The Author(s).

PY - 2021/6/8

Y1 - 2021/6/8

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.

UR - https://www.scopus.com/pages/publications/85107830538

U2 - 10.1038/s41467-021-23717-5

DO - 10.1038/s41467-021-23717-5

M3 - Article

C2 - 34103493

AN - SCOPUS:85107830538

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3464

ER -

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Abstract

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