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Epithelial calcineurin controls microbiota-dependent intestinal tumor development.

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Peuker, Kenneth 
Muff, Stefanie 
Künzel, Sven 
Bosse, Esther 


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.



Animals, Blotting, Western, Calcineurin, Cell Proliferation, Cell Survival, Colorectal Neoplasms, Disease Models, Animal, Electrophoretic Mobility Shift Assay, Epithelial Cells, Fecal Microbiota Transplantation, Flow Cytometry, Gastrointestinal Microbiome, Genes, APC, HCT116 Cells, HT29 Cells, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Intestinal Mucosa, Intestinal Neoplasms, Intestines, Mice, NFATC Transcription Factors, Neoplastic Stem Cells, Organoids, Prognosis, RNA, Ribosomal, 16S, Reverse Transcriptase Polymerase Chain Reaction, Tissue Array Analysis

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Nat Med

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Springer Science and Business Media LLC
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.).