Antithetical NFATc1-Sox2 and p53-miR-200 signalling networks governs pancreatic cancer cell plasticity and tumour progression

• Published in: Zeitschrift für Gastroenterologie
• Main Authors: Hessmann, E, Singh, SK, Chen, NM, König, A, Esposito, I, Lahmann, M, Neesse, A, Vogt, S, Völker, N, Ellenrieder, V
• Format: Conference Proceeding
• Language: English; German
• Published: 11.08.2014
• ISSN: 0044-2771; 1439-7803
• DOI: 10.1055/s-0034-1385985

Introduction: Pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transdifferentiation (EMT) in adaption to environmental signals, including inflammation, a process that combines tumour cell dedifferentiation with dissemination and acquisition of stemness features. However, the mechanisms coupling inflammation-induced signalling pathways with EMT and stemness remain largely unknown. 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 and how NFATc1 controls transcription of EMT and stemness genes in PDAC. Methods: We generated and characterized mouse strains with combined pancreas-specific expression of Kras G12D , p53 R172 H or p53 fl/wt and NFATc1 using Cre-Lox technology. Murine 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: We show that NFATc1 drives EMT programming and maintains pancreatic cancer cells in a stem cell-like state through Sox2-dependent transcriptional activation of critical EMT and stemness factors. Intriguingly, NFATc1-Sox2 complex mediated PDAC dedifferentiation and progression is opposed by antithetical p53-miR200c signalling and inactivation of the tumour suppressor pathway is required for tumour dissemination and dedifferentiation both in genetically engineered mouse models and human PDAC. Conclusion: Our results provide a novel mechanistic link between oncogenic inflammatory environmental signals and gain of stemness features and EMT in PDAC and highlight that pharmacological inactivation of NFATc1-Sox2 signalling might hold great therapeutic impact addressing metastasis and chemoresistance in pancreatic cancer. Freie Vorträge – unsere Besten Donnerstag, 18. September 2014/17:00 – 18:30/Saal 2