Charakterisierung eines transgenen Mausmodells zur Kooperation zwischen NFATc1 und KrasG12D in der Pankreaskarzinogenese

The Nuclear Factor of Activated T-Cells (NFAT) c1 is an oncogenic transcription factor, which is frequently overexpressed in pancreatic cancer. NFATc1 controls the expression of critical cell-cycle regulators in cooperation with different partner proteins, thereby enhancing tumor growth. The pro-proliferative function of NFATc1 has been shown in a previous transgenic mouse model. However, the expression of constitutive active NFATc1 (c.n.NFATc1) in the pancreas neither stimulated the formation of PanIN lesions typical for human pancreatic cancer nor caused development of invasive carcinomas. The mutation of the proto-oncogene Kras is found in the vast majority of pancreatic cancers, where it is considered the initiating event. In genetically modified mice, Kras induces formation of precursor lesions but promotes cancer development with only low frequency. Therefore, additional genetic or epigenetic events are required for the progression to invasive cancer. The aim of this thesis was to investigate and characterize the oncogenic cooperation between NFATc1 and KrasG12D in vivo and to explore the underlying mechanisms. To this end, both oncogenes were co-expressed in the exocrine pancreas of transgenic mice. Here, we demonstrate that combined expression of c.n.NFATc1 and KrasG12D in pancreata of mice (c.n.NFATc1;KrasG12D;P48/PDX1-Cre) leads to massive acceleration of pancreatic carcinogenesis, causing formation of acinar-ductal metaplasia, PanIN1-3 lesions, and the development of invasive pancreatic cancer. In analogy to human pancreatic carcinogenesis, combined expression of both oncogenes resulted in marked cell proliferation and activation of oncogenic pathways such as the Notch- signaling pathway. Disruption of Kras-induced and p16INK4A -dependent senescence appears to contribute to cancer progression. In conclusion, a massive acceleration of Kras-induced carcinogenesis due to oncogenic cooperation with NFATc1 could be depicted. Thus, the great importance of the Ca2+/Calcineurin/NFATc1-signaling pathway as a target for therapy of pancreatic cancer was underlined.