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

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 R. Greten, Gareth J. Inman, Owen J. Sansom (Lead / Corresponding author)

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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 Kras(G12D/+) 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.Cell Death and Differentiation advance online publication, 16 June 2017; doi:10.1038/cdd.2017.92.

    Original languageEnglish
    Pages (from-to)1681-1693
    Number of pages13
    JournalCell Death & Differentiation
    Volume24
    Issue number10
    Early online date16 Jun 2017
    DOIs
    Publication statusPublished - Oct 2017

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    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., & Sansom, O. J. (2017). TGFβ pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis. Cell Death & Differentiation, 24(10), 1681-1693. https://doi.org/10.1038/cdd.2017.92