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

共 78 条

[11] Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
Calon, Alexandre
Espinet, Elisa
Palomo-Ponce, Sergio
Tauriello, Daniele V. F.
Iglesias, Mar
Virtudes Cespedes, Maria
Sevillano, Marta
Nadal, Cristina
Jung, Peter
Zhang, Xiang H. -F.
Byrom, Daniel
Riera, Antoni
Rossell, David
Mangues, Ramon
Massague, Joan
Sancho, Elena
Batlle, Eduard
[J]. CANCER CELL, 2012, 22 (05) : 571 - 584
[12] TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis
Cammareri, Patrizia
Vincent, David F.
Hodder, Michael C.
Ridgway, Rachel A.
Murgia, Claudio
Nobis, Max
Campbell, Andrew D.
Varga, Julia
Huels, David J.
Subramani, Chithra
Prescott, Katie Lh
Nixon, Colin
Hedley, Ann
Barry, Simon T.
Greten, Florian R.
Inman, Gareth J.
Sansom, Owen J.
[J]. CELL DEATH AND DIFFERENTIATION, 2017, 24 (10) : 1681 - 1693
[13] Colorectal premalignancy is associated with consensus molecular subtypes 1 and 2
Chang, K.
Willis, J. A.
Reumers, J.
Taggart, M. W.
Lucas, F. A. San
Thirumurthi, S.
Kanth, P.
Delker, D. A.
Hagedorn, C. H.
Lynch, P. M.
Ellis, L. M.
Hawk, E. T.
Scheet, P. A.
Kopetz, S.
Arts, J.
Guinney, J.
Dienstmann, R.
Vilar, E.
[J]. ANNALS OF ONCOLOGY, 2018, 29 (10) : 2061 - 2067
[14] Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic Tumorigenesis
Chuvin, Nicolas
Vincent, David F.
Pommier, Roxane M.
Alcaraz, Lindsay B.
Gout, Johann
Caligaris, Cassandre
Yacoub, Karam
Cardot, Victoire
Roger, Elodie
Kaniewski, Bastien
Martel, Sylvie
Cintas, Celia
Goddard-Leon, Sophie
Colombe, Amelie
Valantin, Julie
Gadot, Nicolas
Servoz, Emilie
Morton, Jennifer
Goddard, Isabelle
Couvelard, Anne
Rebours, Vinciane
Guillermet, Julie
Sansom, Owen J.
Treilleux, Isabelle
Valcourt, Ulrich
Sentis, Stephanie
Dubus, Pierre
Bartholin, Laurent
[J]. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 2017, 4 (02): : 263 - 282
[15] Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche
Davis, Hayley
Irshad, Shazia
Bansal, Mukesh
Rafferty, Hannah
Boitsova, Tatjana
Bardella, Chiara
Jaeger, Emma
Lewis, Annabelle
Freeman-Mills, Luke
Giner, Francesc C.
Rodenas-Cuadrado, Pedro
Mallappa, Sreelakshmi
Clark, Susan
Thomas, Huw
Jeffery, Rosemary
Poulsom, Richard
Rodriguez-Justo, Manuel
Novelli, Marco
Chetty, Runjan
Silver, Andrew
Sansom, Owen J.
Greten, Florian R.
Wang, Lai Mun
East, James E.
Tomlinson, Ian
Leedham, Simon J.
[J]. NATURE MEDICINE, 2015, 21 (01) : 62 - 70
[16] Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification
Dunne, Philip D.
Alderdice, Matthew
O'Reilly, Paul G.
Roddy, Aideen C.
McCorry, Amy M. B.
Richman, Susan
Maughan, Tim
McDade, Simon S.
Johnston, Patrick G.
Longley, Daniel B.
Kay, Elaine
Mcart, Darragh G.
Lawler, Mark
[J]. NATURE COMMUNICATIONS, 2017, 8
[17] Tissue-specific and inducible Cre-mediated recombination in the gut epithelium
El Marjou, F
Janssen, KP
Chang, BHJ
Li, M
Hindie, V
Chan, L
Louvard, D
Chambon, P
Metzger, D
Robine, S
[J]. GENESIS, 2004, 39 (03) : 186 - 193
[18] TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype
Fessler, Evelyn
Drost, Jarno
van Hooff, Sander R.
Linnekamp, Janneke F.
Wang, Xin
Jansen, Marnix
Melo, Felipe De Sousa E.
Prasetyanti, Pramudita R.
Ijspeert, Joep E. G.
Franitza, Marek
Nurnberg, Peter
van Noesel, Carel J. M.
Dekker, Evelien
Vermeulen, Louis
Clevers, Hans
Medema, Jan Paul
[J]. EMBO MOLECULAR MEDICINE, 2016, 8 (07) : 745 - 760
[19] Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation
Fischer, Jared M.
Calabrese, Peter P.
Miller, Ashleigh J.
Munoz, Nina M.
Grady, William M.
Shibata, Darryl
Liskay, R. Michael
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (43) : 12192 - 12197
[20] SMAD2, SMAD3 and SMAD4 Mutations in Colorectal Cancer
Fleming, Nicholas I.
Jorissen, Robert N.
Mouradov, Dmitri
Christie, Michael
Sakthianandeswaren, Anuratha
Palmieri, Michelle
Day, Fiona
Li, Shan
Tsui, Cary
Lipton, Lara
Desai, Jayesh
Jones, Ian T.
McLaughlin, Stephen
Ward, Robyn L.
Hawkins, Nicholas J.
Ruszkiewicz, Andrew R.
Moore, James
Zhu, Hong-Jian
Mariadason, John M.
Burgess, Antony W.
Busam, Dana
Zhao, Qi
Strausberg, Robert L.
Gibbs, Peter
Sieber, Oliver M.
[J]. CANCER RESEARCH, 2013, 73 (02) : 725 - 735

← 1 2 3 4 5 6 7 8 →