Charakterisierung des STAT3-Signalwegs in der NFATc1-abhängigen Genese und Progression des Pankreaskarzinoms

The ductal adenocarcinoma of the pancreas is one of the most aggressive solid tumors and known for both its resistance against common chemotherapeutics and its poor prog-nosis. Detailed analysis of the mechanism that leads to the development of pancreatic cancer have underlined the significance of inflammatory pathways in development and progression of this malignancy. Existing data published by our group has identified NFATc1 as an important player in the inflammation-driven carcinogenesis of the pan-creas. Furthermore, molecular analyses of both in vivo and in vitro models have shown that NFATc1 is expressed in the majority of human pancreatic adenocarcinomas and interacts with the inflammatory transcription factor STAT3. Together, they control the expression of oncogenes during the progression of pancreatic cancer. As a consequence, the aims of this thesis were not only to examine the detailed mech-anisms of NFATc1:STAT3 dependent gene regulation, but also to scrutinize the biologi-cal relevance of this oncogenic complex in a transgenic mouse model with a conditional loss of STAT3 in the context of KRASG12D and NFATc1 activation in the pancreas. The data published in this thesis show that the NFATc1 dependent transcriptional regu-lation of oncogenic signatures is the consequence of an enhancer augmented binging of NFATc1. In contrast to that, ChIP-analysis identified that the NFATc1 binding partner STAT3 preferably binds to promoter regions of NFATc1 controlled target genes. Further-more, both the NFATc1 binding to the target genes and their transcriptional activation are strongly regulated by the Interleukin-6-STAT3-pathway. These results propose en-hancer-promotor-loop-formation as a likely mechanism of NFATc1:STAT3 dependent transcriptional control of oncogene expression in pancreatic cancer. To underline the biological significance of these findings in vivo, we created a transgenic mouse model with constitutive activations of KRAS and NFATc1 and a loss of pancreatic STAT3 expression. Surprisingly, these mice showed a more rapid pancreatic cancer pro-gression and a median survival time of only 60 days compared to their littermates without a pancreatic loss of STAT3. Morphologically, the tumors of the STAT3 depriviant mice where hallmarked with a sig-nificant increase in the proportion of tumor stroma. The results presented here underline the oncogenic function of NFATc1 in pancreatic cancer development and progression and identified complex formation with STAT3 as a central transcriptional mechanism in the control of oncogenic gene signatures in inflam-mation-induced pancreatic cancer. Despite of the identification of NFATc1 as a promising target in pancreatic cancer therapy, therapeutic strategies to pharmacologically in-hibit NFATc1 activity in pancreatic cancer cells are missing. In the context of promising clinical trials dealing with the inhibition of the JAK/STAT3 pathway in the therapy of pan-creatic cancer and the herein described central role of STAT3 in NFATc1 dependent transcription, the pharmacological inhibition of the NFATc1 binding partner STAT3 seems to be a promising indirect therapeutic target to block NFATc1 mediated pancreatic cancer progression. Contrarily, the accelerated tumor progression in the STAT3-deficient mouse model in the setting of a constitutive NFATc1 activation suggests that the inhibi-tion of the JAK/STAT3 pathway is only efficient in NFATc1-negative pancreatic cancers. These finding underline the necessity of a molecular therapeutic stratification of pancre-atic cancer patients.