TY  - JOUR
A1  - Cammareri, Patrizia
A1  - Vincent, David F.
A1  - Hodder, Michael C.
A1  - Ridgway, Rachel A.
A1  - Murgia, Claudio
A1  - Nobis, Max
A1  - Campbell, Andrew D.
A1  - Varga, Julia
A1  - Huels, David J.
A1  - Subramani, Chithra
A1  - Prescott, Katie L. H.
A1  - Nixon, Colin
A1  - Hedley, Ann
A1  - Barry, Simon T.
A1  - Greten, Florian
A1  - Inman, Gareth J.
A1  - Sansom, Owen J.
T1  - TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis
T2  - Cell death and differentiation
N2  - 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.
KW  - Cancer genetics
KW  - Cancer models
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46816
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-468162
SN  - 1476-5403
SN  - 1350-9047
N1  - Rights and permissions: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
VL  - 24
IS  - 10
SP  - 1681
EP  - 1693
PB  - Nature Publishing Group ; Macmillan
CY  - Houndmills, Basingstoke ; London
ER  -