ID: 1413. Dual specificity kinase TTK in pancreatic neuroendocrine cancer Marina Hutzler , Harald Schmidt , Brajesh Kaistha , Rita Lawlor , Aldo Scarpa , Thomas Gress , Malte Buchholz 1 Gastroenterology and Endocrinology, Philipps University Marburg, Marburg, Germany Dipartimento ad Attivit a Integrata (DAI) di Patologia e Diagnostica, University of Verona, Verona, Italy Introduction: Pancreatic neuroendocrine tumours are a rare but still very challenging disease, as despite ongoing research, surgical resection still is the only reliable cure. Therefore, about 80 % of patients have a terminal illness and their tumours are still difficult to manage with the currently available chemoand biotherapies obtaining tumour growth stabilization rather than inducing regression. Gene expression analyses of primary tissues from PNET patients identified a number of potential target genes for the development of new therapeutic strategies. Amongst others, we found strong upregulation of the dual specificity kinase TTK, which has been shown before to play an important role during mitosis by inhibiting transition to anaphase until all chromosomes have been attached to the spindle apparatus correctly. Aims: The aim of this study is to elucidate the role of TTK and its value for PNET therapy. Materials & methods: Quantitative realtime PCR, RNAi, cell proliferation and viability assays, Westernblots Results: TTK is strongly overexpressed in pancreatic neuroendocrine tumour tissue. Functional in vitro analyses by siRNA-mediated knockdown of TTK in human as well as in rat PNET cell lines resulted in decreased proliferation and viability of cells, leading to increased apoptosis rates which could be further confirmed by Westernblot analyses of key molecules of the classical apoptosis pathway (Caspase-3 and PARP cleavage). Conclusion: Overexpression of TTK dual specificity kinase in pancreatic neuroendocrine tumours is important for proliferative phenotype of tumour cells and inhibition of TTK leads to apoptotic cell death. Therefore TTK could be a promising target for the treatment of neuroendocrine tumours. Abstract ID: 1416, Oral-3.ID: 1416, Oral-3. Context-dependent epigenetic regulation of NFATc1 transcription in pancreatic plasticity Elisabeth Hessmann , Nai-ming Chen , Clara Lubeseder-Martellato , Jochen Gaedcke , Jens Siveke , Albrecht Neesse , Volker Ellenrieder 1 Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Germany 2 II. Med. Klinikum rechts der Isar, TU Munich, Germany Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Germany West German Cancer Center Essen, Germany Introduction: Cellular plasticity of the pancreas highly contributes to its enormous regenerative potential upon acinar insults, but also causes therapeutic resistance in pancreatic cancer (PDAC) treatment. On the molecular level, regulation of cellular plasticity involves epigenetic mechanisms that transcriptionally control key-signatures of tissue adaptation. Transcriptional activation of the oncogenic Nuclear Factor of Activated T-cell (NFAT) c1 transcription factor significantly contributes to PDAC cell plasticity. Nevertheless, how epigenetic alterations converge on transcriptional regulation of NFATc1 remains elusive. Aims: To investigate how epigenetic regulation impacts on NFATc1 transcription in pancreatic plasticity. Materials&methods: NFATc1 function and regulationwere studied in the regenerative pancreas upon caerulein-induced acinar cell damage and in various in vitroand in vivo PDAC-models. EZH2-dependency of NFATc1 expression was determined upon genetic or pharmacological EZH2Abstracts / Pancreato S10 inhibition. NFATc1 promoter activity was investigated by ChIP-Assays in pancreatic tissue and cells. Co-expression of EZH2 and NFATc1 was validated in micro-dissected PDAC cells from human samples. Results: Pancreatic tissue regeneration requires silencing of the NFATc1 promoter by the Polycomb-Repressor-Complex member EZH2 to circumvent organ atrophy and exocrine insufficiency. In contrast, EZH2 activation in PDAC shows inverse effects on NFATc1 promoter regulation and promotes PDAC cell plasticity by enhancing NFATc1 transcription. Oncogenic mutation of Kraswas identified as the crucial genetic hit responsible for the functional switch in EZH2-dependent regulation of NFATc1 transcription. Conclusion: These data complement previous descriptions of Polycomb-independent EZH2 functions and emphasize how epigenetic mechanisms integrate into genomic alterations in PDAC. Consequently, pharmacological inhibition of EZH2 represents a beneficial strategy to overcome oncogenic NFATc1 activity in PDAC.