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 Greten, Gareth J. Inman, Owen J. Sansom
- 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.
MetadatenAuthor: | 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 |
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URN: | urn:nbn:de:hebis:30:3-468162 |
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DOI: | https://doi.org/10.1038/cdd.2017.92 |
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ISSN: | 1476-5403 |
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ISSN: | 1350-9047 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/28622298 |
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Parent Title (English): | Cell death and differentiation |
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Publisher: | Nature Publishing Group ; Macmillan |
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Place of publication: | Houndmills, Basingstoke ; London |
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Contributor(s): | G. Melino |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2017 |
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Date of first Publication: | 2017/06/16 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2018/06/21 |
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Tag: | Cancer genetics; Cancer models |
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Volume: | 24 |
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Issue: | 10 |
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Page Number: | 13 |
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First Page: | 1681 |
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Last Page: | 1693 |
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Note: | 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/ |
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HeBIS-PPN: | 43423687X |
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Institutes: | Medizin / Medizin |
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| Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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