TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis

Cammareri, P. et al. (2017) TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis. Cell Death and Differentiation, 24(10), pp. 1681-1693. (doi:10.1038/cdd.2017.92) (PMID:28622298)

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Abstract

Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-κB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFβ signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFβ type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFβ and blockade of these makes tumourigenesis more efficient from this compartment.

Item Type:Articles
Additional Information:OJS is supported by a Cancer Research UK core grant (A21139) and an ERC starting grant (311301). GJI was supported by a Cancer Research UK programme grant (A21358) and an ERC grant (250170). PC is supported by FP7 Health CP-IP - Large-scale integrating project grant (278568), DFV is supported by ERC Starting grant (311301).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cammareri, Dr Patrizia and Nixon, Mr Colin and Campbell, Mr Andrew and Vincent, Dr David and Subramani, Miss Chithra and Murgia, Dr Claudio and Ridgway, Dr Rachel and Inman, Professor Gareth and Sansom, Professor Owen and Hodder, Michael
Authors: Cammareri, P., Vincent, D. F., Hodder, M. C., Ridgway, R. A., Murgia, C., Nobis, M., Campbell, A. D., Varga, J., Huels, D. J., Subramani, C., Prescott, K. L.H., Nixon, C., Hedley, A., Barry, S. T., Greten, F. R., Inman, G. J., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Death and Differentiation
Publisher:Nature Publishing Group
ISSN:1350-9047
ISSN (Online):1476-5403
Published Online:16 June 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Cell Death and Differentiation 24(10):1681-1693
Publisher Policy:Reproduced under a Creative Commons License

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