Mechanismen der NFATc1-abhängigen Regulation von Stammzelleigenschaften im Pankreaskarzinom

Important causes for the poor prognosis of pancreatic cancer are in particular its aggressive growth pattern and its distinct resistance against chemotherapy. Both features are associated with a dedifferentiated phenotype and the acquisition of stem cell features. The transformation into stem cell-like cancer cells is accompanied by the activation of specific gene signatures as well as by the induction of certain stem cell factors (Sox2, Klf4, Oct4, Nanog and Bmi1). The loss of the tumour suppressor p53 is considered as a key event in dedifferentiation and acquisition of stem cell features and is observed in 75 % of all human pancreatic cancers. This specifically applies to tumours with activation of the oncogenic transcription factor NFATc1, which is also expressed in the majority of human pancreatic cancers and contributes to dissemination and metastatic spread. The main focus of this work was the regulation of stem cell features in pancreatic cancer by a not yet described, antagonistic p53-NFATc1 signaling pathway. It could be shown that the function of NFATc1 in pancreatic cancer is defined by p53. The loss of p53 leads to acquisition of stem cell features by NFATc1-dependent activation of Sox2 and other stem cell factors. NFATc1 induces Sox2 expression by direct promotor and enhancer binding and simultaneous recruitment of RNA polymerase II. To allow NFATc1-Sox2-dependent acquisition of stem cell features, inhibition of the dominating p53-microRNA-200c signaling pathway, which inhibits activation of Sox2 and other stem cell factors, is required. In conclusion, the results of this work contribute to a better understanding of the molecular mechanisms of tumour progression of pancreatic cancer and show that central elements of cell plasticity and regulation of stem cell features are regulated by a hierarchically structured network. The knowledge that the frequently observed loss of p53 leads to acquisition of stem cell features on the basis of activation of NFATc1-Sox2 signaling pathway might reveal new promising targets for future therapy of pancreatic cancer.