GSK-3beta regulated NFATc1 transcription complexes in pancreatic carcinogenesis and drug resistance

• Applicant: Professor Dr. Andreas Burchert, since 7/2014
• Subject Area: Hematology, Oncology
• Term: from 2008 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 59021035

A better understanding of the molecular carcinogenesis and in particular of mechanisms that convey resistance to conventional cytotoxic therapy is urgently needed to develop more effective therapeutic strategies to defend pancreatic cancer. Growing evidence suggests that mutational activation of oncogenic K-Ras initiates pancreatic carcinogenesis but requires additional genetic, epigenetic and signaling events to overcome cellular defense mechanisms and promote premalignant lesions towards invasively growing cancers. One such critical event is the ectopic induction and activation of NFAT transcription factors which control key aspects of carcinogenesis through their ability to integrate signals from other transcription pathways into specific gene responses. In the first funding period we focused on signaling regulation of NFAT factors in pancreatic cancer and identified the serine/threonine kinase GSK-3b as a master regulator of NFAT stability and transcription. GSK-3b targets nuclear NFAT factors for phosphorylation dependent stabilization in pancreatic cancer cells and in addition, promotes complex formation with the oncogenic transcription factors NF-ĸB and Signal transducer and activator of transcription 3 (STAT3). In the next funding period, we take advantage of genetic engineered mice (P48+/Cre;LSL-KrasG12D/+;NFATc1 (NKC mice)) with pancreas specific expression of KrasG12D and NFATc1. This transgenic mice model recapitulates the human disease and develops stepwise transformation of exocrine pancreatic epithelium to preinvasive precursor lesions and invasively growing cancers. We will employ this tumor model and primary cell lines to comprehensively characterize the mechanisms, function and GSK-3β dependent regulation of NFAT-(NF-ĸB/STAT3) complex formation in gene transcription during pancreatic carcinogenesis and drug resistance.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 210: Genetics of Drug Resistance in Cancer
• Ehemaliger Antragsteller: Professor Dr. Volker Ellenrieder, until 6/2014