Epithelial calcineurin controls microbiota-dependent intestinal tumor developmentReport as inadecuate


Epithelial calcineurin controls microbiota-dependent intestinal tumor development


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Publication Date: 2016-04-04

Journal Title: Nature Medicine

Publisher: Nature Publishing Group

Volume: 22

Pages: 506-515

Language: English

Type: Article

This Version: AM

Metadata: Show full item record

Citation: Peuker, K., Muff, S., Wang, J., Künzel, S., Bosse, E., Zeissig, Y., Luzzi, G., et al. (2016). Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nature Medicine, 22 506-515. https://doi.org/10.1038/nm.4072

Description: This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nm.4072

Abstract: Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell–intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.

Keywords: cancer stem cells, colon cancer

Sponsorship: This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grants ZE814/5-1 (S.Z.), BA2863/5-1 (J.F.B.) and CH279/5-1 (T.C.), the European Research Council (ERC) starting grant 336528 (S.Z.), a Postdoctoral Fellowship Award from the Crohn's and Colitis Foundation of America (S.Z.), the European Commission (Marie Curie International Reintegration grant 256363; S.Z.), the DFG Excellence Cluster 'Inflammation at Interfaces' (S.Z. and J.F.B.), the DFG Excellence Cluster 'Center for Regenerative Therapies' (S.Z.); the US National Institutes of Health grants DK044319 (R.S.B.), DK051362 (R.S.B.), DK053056 (R.S.B.) and DK088199 (R.S.B.), the Harvard Digestive Diseases Center (HDDC) grant DK0034854 (R.S.B.), and the AIRC grant IG-14233 (M.E.B.).

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External DOI: https://doi.org/10.1038/nm.4072

This record's URL: https://www.repository.cam.ac.uk/handle/1810/257003







Author: Peuker, KennethMuff, StefanieWang, JunKünzel, SvenBosse, EstherZeissig, YvonneLuzzi, GiuseppinaBasic, MarijanaStrigli, AnneUlbric

Source: https://www.repository.cam.ac.uk/handle/1810/257003



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