Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity

Shiv K. Singh, Nai Ming Chen, Elisabeth Hessmann, Jens Siveke, Marlen Lahmann, Garima Singh, Nadine Voelker, Sophia Vogt, Irene Esposito, Ansgar Schmidt, Cornelia Brendel, Thorsten Stiewe, Jochen Gaedcke, Marco Mernberger, Howard C. Crawford, William R. Bamlet, Jin San Zhang, Xiao Kun Li, Thomas C. Smyrk, Daniel D. BilladeauMatthias Hebrok, Albrecht Neesse, Alexander Koenig, Volker Ellenrieder

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

In adaptation to oncogenic signals, pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transition (EMT), a process combining tumor cell dedifferentiation with acquisition of stemness features. However, the mechanisms linking oncogene-induced signaling pathways with EMT and stemness remain largely elusive. Here, we uncover the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity. In particular, we show that NFATc1 drives EMT reprogramming and maintains pancreatic cancer cells in a stem cell-like state through Sox2-dependent transcription of EMT and stemness factors. Intriguingly, NFATc1-Sox2 complex-mediated PDAC dedifferentiation and progression is opposed by antithetical p53-miR200c signaling, and inactivation of the tumor suppressor pathway is essential for tumor dedifferentiation and dissemination both in genetically engineered mouse models (GEMM) and human PDAC. Based on these findings, we propose the existence of a hierarchical signaling network regulating PDAC cell plasticity and suggest that the molecular decision between epithelial cell preservation and conversion into a dedifferentiated cancer stem cell-like phenotype depends on opposing levels of p53 and NFATc1 signaling activities.

Original languageEnglish (US)
Pages (from-to)517-530
Number of pages14
JournalEMBO Journal
Volume34
Issue number4
DOIs
StatePublished - Feb 12 2015

Keywords

  • Cellular plasticity
  • NFATc1
  • Sox2
  • miRNA
  • p53

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Singh, S. K., Chen, N. M., Hessmann, E., Siveke, J., Lahmann, M., Singh, G., Voelker, N., Vogt, S., Esposito, I., Schmidt, A., Brendel, C., Stiewe, T., Gaedcke, J., Mernberger, M., Crawford, H. C., Bamlet, W. R., Zhang, J. S., Li, X. K., Smyrk, T. C., ... Ellenrieder, V. (2015). Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity. EMBO Journal, 34(4), 517-530. https://doi.org/10.15252/embj.201489574