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Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms

Oncogene volume 33, pages 1840–1849 (2014)Cite this article

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Abstract

NFAT (the nuclear factor of activated T cells) upregulation has been linked to cellular transformation intrinsically, but it is unclear whether and how tissue cells with NFAT activation change the local environment for tumor initiation and progression. Direct evidence showing NFAT activation initiates primary tumor formation in vivo is also lacking. Using inducible transgenic mouse systems, we show that tumors form in a subset of, but not all, tissues with NFATc1 activation, indicating that NFAT oncogenic effects depend on cell types and tissue contexts. In NFATc1-induced skin and ovarian tumors, both cells with NFATc1 activation and neighboring cells without NFATc1 activation have significant upregulation of c-Myc and activation of Stat3. Besides known and suspected NFATc1 targets, such as Spp1 and Osm, we have revealed the early upregulation of a number of cytokines and cytokine receptors, as key molecular components of an inflammatory microenvironment that promotes both NFATc1+ and NFATc1− cells to participate in tumor formation. Cultured cells derived from NFATc1-induced tumors were able to establish a tumorigenic microenvironment, similar to that of the primary tumors, in an NFATc1-dependent manner in nude mice with T-cell deficiency, revealing an addiction of these tumors to NFATc1 activation and downplaying a role for T cells in the NFATc1-induced tumorigenic microenvironment. These findings collectively suggest that beyond the cell autonomous effects on the upregulation of oncogenic proteins, NFATc1 activation has non-cell autonomous effects through the establishment of a promitogenic microenvironment for tumor growth. This study provides direct evidence for the ability of NFATc1 in inducing primary tumor formation in vivo and supports targeting NFAT signaling in anti-tumor therapy.

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Acknowledgements

We thank Dr Crabtree for providing the TetO-NFATc1Nuc mice and Dr Yuan Zhu for helpful discussion of the study. FC is supported in part by institutional funds from the Department of Medicine at Washington University School of Medicine and NIH grants (DK81592 and DK67386). We also thank the George M. O’Brien Center for Kidney Disease Research at Washington University (P30DK079333) for core services. We thank Michael Heinz from the Genome Technology Access Center (P30 CA91842, UL1RR024992) in the Department of Genetics at Washington University School of Medicine for help with gene expression analysis.

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Authors and Affiliations

  1. Department of Medicine, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA

    P Tripathi, Y Wang, M Coussens, K R Manda, A M Casey, C Lin, L Ma & F Chen

  2. Department of Bioengineering, Washington University School of Medicine, St. Louis, MO, USA

    E Poyo

  3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    J D Pfeifer

  4. Department of Biology, University of Maryland, Baltimore, MD, USA

    N Basappa

  5. Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    C M Bates

  6. Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA

    H Zhang

  7. Division of Oncology, Kaiser Permanente Medical Center, Santa Clara, CA, USA

    M Pan

  8. Department of Medicine, The Genome Institute, Washington University School of Medicine, St. Louis, MO, USA

    L Ding

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  1. P Tripathi
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Correspondence to F Chen.

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Tripathi, P., Wang, Y., Coussens, M. et al. Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms. Oncogene 33, 1840–1849 (2014). https://doi.org/10.1038/onc.2013.132

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