Z Gastroenterol 2013; 51 - K209
DOI: 10.1055/s-0033-1352849

Antidromic NFATc1 and p53 signaling at the edge of differentiation and stemness in pancreatic cancer

SK Singh 1, S Vogt 1, N Völker 1, B Geisel 1, NM Chen 1, E Glesel 1, K Reutlinger 1, G Singh 1, S Baumgart 1, TM Gress 1, V Ellenrieder 1
  • 1Philipps-Universität Marburg, Klinik für Innere Medizin, Abteilung Gastroenterologie, Marburg, Germany

Introduction: The current concept suggests a direct link between EMT and stemness induction in pancreatic cancer, thereby coupling cell motility and de-differentiation with self-renewal capacities and drug resistance. Both key features of cellular plasticity are controlled by distinct intracellular signaling and transcription pathways. We have shown that activation of the NFATc1 transcription factor promotes pancreatic cancer development and metastasis through its ability to integrate extrinsic stimuli into coordinated gene regulation.

Aim: To assess whether NFATc1 controls transcription of EMT genes and stemness in PDAC, particularly upon p53 inactivation.

Methods: We generated mouse strains with combined pancreas-specific expression of NFATc1, p53 R172 H and KrasG12D using Cre-Lox technology. These mice showed a highly aggressive tumor growth (median survival of < 50 days). Mouse primary tumour cells were used to identify NFATc1 targets by gene expression profiling and pathway analyses (ChIP seq, miRNA analyses and GSEA). NFATc1 mediated EMT and stemness were assessed in human and murine pancreatic cancer models using migration and spheroid assay as well as xenograft mouse models.

Results: Here, we identified antidromic NFATc1 and p53 signaling pathways in transcriptional control over EMT and stemness. We show that p53 activation prevents cells from EMT in a miR200 dependent manner. However, disruption of the tumor suppressor pathway enables NFATc1/Sox2 chromatin complex formation and transcription of EMT programmes, resulting in highly invasive and metastatic PDACs. Finally, re-expression of miR200c or NFATc1 inactivation suppresses EMT/stemness genes and re-sensitizes PDAC to chemotherapy.

Conclusion: Antidromic NFATc1 and p53 signaling pathways control key features of cellular plasticity and tumor progression at the level of gene transcription. These findings implicate key roles for NFATc1 in transcriptional regulation of differentiation and self-renewal in PDAC.