Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

被引：10

作者：

Flanagan, Dustin J. ^{[1
,2
,3
]}

Amirkhah, Raheleh ^{[4
]}

Vincent, David F. ^{[1
]}

Gunduz, Nuray ^{[1
]}

Gentaz, Pauline ^{[1
]}

Cammareri, Patrizia ^{[1
]}

McCooey, Aoife J. ^{[4
]}

McCorry, Amy M. B. ^{[4
]}

Fisher, Natalie C. ^{[4
]}

Davis, Hayley L. ^{[5
]}

Ridgway, Rachel A. ^{[1
]}

Lohuis, Jeroen ^{[6
]}

Leach, Joshua D. G. ^{[1
,7
]}

Jackstadt, Rene ^{[1
,8
,9
]}

Gilroy, Kathryn ^{[1
]}

Mariella, Elisa ^{[10
]}

Nixon, Colin ^{[1
]}

Clark, William ^{[1
]}

Hedley, Ann ^{[1
,11
]}

Markert, Elke K. ^{[1
,7
]}

Strathdee, Douglas ^{[1
]}

Bartholin, Laurent ^{[12
]}

Redmond, Keara L. ^{[4
]}

Kerr, Emma M. ^{[4
]}

Longley, Daniel B. ^{[4
]}

Ginty, Fiona ^{[13
]}

Cho, Sanghee ^{[13
]}

Coleman, Helen G. ^{[4
,14
]}

Loughrey, Maurice B. ^{[4
,14
,15
]}

Bardelli, Alberto ^{[10
]}

Maughan, Timothy S. ^{[16
]}

Campbell, Andrew D. ^{[1
]}

Lawler, Mark ^{[4
]}

Leedham, Simon J. ^{[5
]}

Barry, Simon T. ^{[17
]}

Inman, Gareth J. ^{[1
,7
]}

van Rheenen, Jacco ^{[6
]}

Dunne, Philip D. ^{[1
,4
]}

Sansom, Owen J. ^{[1
,7
]}

机构：

[1] Canc Res UK Beatson Inst, Glasgow, Lanark, Scotland

[2] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic, Australia

[3] Monash Univ, Biomed Discovery Inst, Canc Program, Melbourne, Vic, Australia

[4] Queens Univ Belfast, Patrick G Johnston Ctr Canc Res, Belfast, Antrim, North Ireland

[5] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[6] Netherlands Canc Inst, Oncode Inst, Dept Mol Pathol, Amsterdam, Netherlands

[7] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland

[8] Heidelberg Inst Stem Cell Technol & Expt Med HIST, Heidelberg, Germany

[9] Deutsch Krebsforschungszentrum DKFZ, Heidelberg, Germany

[10] Univ Torino, Dept Oncol, Candiolo Torino, Italy

[11] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England

[12] Ctr Rech Cancerol Lyon, INSERM, Lyon, France

[13] GE Global Res Ctr, Niskayuna, NY USA

[14] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland

[15] Belfast Hlth & Social Care Trust, Dept Cellular Pathol, Belfast, Antrim, North Ireland

[16] Univ Oxford, CRUK MRC Oxford Inst Radiat Oncol, Oxford, England

[17] AstraZeneca, Oncol R&D, Biosci, Cambridge, England

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

CONSENSUS MOLECULAR SUBTYPES; COLORECTAL-CANCER; STEM-CELLS; RECEPTOR; EXPRESSION; MUTATIONS; WNT; DEDIFFERENTIATION; MICROENVIRONMENT; PROLIFERATION;

D O I：

10.1038/s41467-022-35134-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The pro-tumourigenic role of epithelial TGF beta signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGF beta signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGF beta signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGF beta signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGF beta signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits.

引用

页数：18

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