Charakterisierung NFATc1-abhängiger transkriptioneller Mechanismen während der inflammationsinduzierten Pankreaskarzinomentstehung

Acinar-to-ductal Metaplasia (ADM) constitutes the first step in pancreatic carcinogenesis . On the molecular level, ADM formation and pancreatic cancer (PDAC) initiation are linked to activating oncogenic mutationof Kras. Although Kras mutations have been characterized as the crucial genetic event in PDAC initiation and progression, exclusive Kras-mutation is not sufficient to drive progression of PDAC precursor lesion beyond the state of premalignancy. Instead, oncogenic activation of Kras cooperates with inflammatory signaling pathways, e.g. in context of chronic pancreatitis to promote pancreatic carcinogenesis. Inflammation-associated activation of the EGFR-signaling pathway has previously been proposed as an essential component of Kras-driven PDAC initiation and progression, although the detailed mechanisms of EGFR-dependent ADM-formation remain elusive. Previous studies of our group characterized the inflammatory transcription factor Nuclear Factor of Activated T-cells c1 (NFATc1) as a pivotal oncogenic driver of pancreatic carcinogenesis and PDAC progression The aim of this thesis was to define the role of NFATc1 in inflammation induced EGFR-dependent PDAC initiation. In vitro and in vivo studies reveales EGFR-dependent NFATc1-expression in metaplastic lesions of the inflammation-challenged pancreas Upon induction of EGFR-signaling, NFATc1 forms a complexwith the AP1-family protein c-Jun at the promoter of the ductal-fate determinant Sox9 for subsequent transcriptional activation, thus inducing acinar-to-ductal transdifferentiation. In contrast, pharmacologic or genetic inhibition of NFATc1 activity effectly blocks Sox9 transcription and prevents EGFR-dependet ADM, thus characterizing NFATc1 as a central mediator of EGFR-dependent PDAC initiation. Therefore, pharmacological approaches that interfere with NFATc1 activation might represent a promising strategy to prevent PDAC development in high risk chronic pancreatitis patients