Epithelial calcineurin controls microbiota-dependent intestinal tumor development

Kenneth Peuker, Stefanie Muff, Jun Wang, Sven Künzel, Esther Bosse, Yvonne Zeissig, Giuseppina Luzzi, Marijana Basic, Anne Strigli, Andrea Ulbricht, Arthur Kaser, Alexander Arlt, Triantafyllos Chavakis, Gijs R. Van Den Brink, Clemens Schafmayer, Jan-Hendrik Egberts, Thomas Becker, Marco E. Bianchi, André Bleich, Christoph RöckenJochen Hampe, Stefan Schreiber, John F. Baines, Richard S. Blumberg, Sebastian Zeissig

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)506 - 515
Number of pages10
JournalNature Medicine
Volume22
Issue number5
DOIs
Publication statusPublished - May 1 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Peuker, K., Muff, S., Wang, J., Künzel, S., Bosse, E., Zeissig, Y., Luzzi, G., Basic, M., Strigli, A., Ulbricht, A., Kaser, A., Arlt, A., Chavakis, T., Van Den Brink, G. R., Schafmayer, C., Egberts, J-H., Becker, T., Bianchi, M. E., Bleich, A., ... Zeissig, S. (2016). Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nature Medicine, 22(5), 506 - 515. https://doi.org/10.1038/nm.4072