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

  • 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.
Author:Patrizia Cammareri, David F. Vincent, Michael C. Hodder, Rachel A. Ridgway, Claudio Murgia, Max Nobis, Andrew D. Campbell, Julia Varga, David J. Huels, Chithra Subramani, Katie L. H. Prescott, Colin Nixon, Ann Hedley, Simon T. Barry, Florian GretenORCiDGND, Gareth J. Inman, Owen J. Sansom
Pubmed Id:
Parent Title (English):Cell death and differentiation
Publisher:Nature Publishing Group ; Macmillan
Place of publication:Houndmills, Basingstoke ; London
Contributor(s):G. Melino
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/06/16
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/06/21
Tag:Cancer genetics; Cancer models
Page Number:13
First Page:1681
Last Page:1693
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Institutes:Medizin / Medizin
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0