Nai-Ming Chen1, Albrecht Neesse1, Moritz Lino Dyck2, Benjamin Steuber1, Alexander O Koenig1, Clara Lubeseder-Martellato3, Thore Winter2, Teresa Forster2, Hanibal Bohnenberger4, Julia Kitz4, Kirsten Reuter-Jessen4, Heidi Griesmann5, Jochen Gaedcke6, Marian Grade6, Jin-San Zhang7, Wan-Chi Tsai8, Jens Siveke9, Hans-Ulrich Schildhaus4, Philipp Ströbel4, Steven A Johnsen6, Volker Ellenrieder1, Elisabeth Hessmann10. 1. Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany. 2. Signaling and Transcription Laboratory, Department of Gastroenterology, Philipp's University, Marburg, Germany. 3. II. Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität, Munich, Germany. 4. Institute of Pathology, University Medical Center Göttingen, Germany. 5. Department of Internal Medicine I, University Medical Center Halle, Germany. 6. Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany. 7. Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota; School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, PR China. 8. Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan. 9. German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. 10. Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany. Electronic address: elisabeth.hessmann@med.uni-goettingen.de.
Abstract
BACKGROUND & AIMS: The ability of exocrine pancreatic cells to change the cellular phenotype is required for tissue regeneration upon injury, but also contributes to their malignant transformation and tumor progression. We investigated context-dependent signaling and transcription mechanisms that determine pancreatic cell fate decisions toward regeneration and malignancy. In particular, we studied the function and regulation of the inflammatory transcription factor nuclear factor of activated T cells 1 (NFATC1) in pancreatic cell plasticity and tissue adaptation. METHODS: We analyzed cell plasticity during pancreatic regeneration and transformation in mice with pancreas-specific expression of a constitutively active form of NFATC1, or depletion of enhancer of zeste 2 homologue 2 (EZH2), in the context of wild-type or constitutively activate Kras, respectively. Acute and chronic pancreatitis were induced by intraperitoneal injection of caerulein. EZH2-dependent regulation of NFATC1 expression was studied in mouse in human pancreatic tissue and cells by immunohistochemistry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. We used genetic and pharmacologic approaches of EZH2 and NFATC1 inhibition to study the consequences of pathway disruption on pancreatic morphology and function. Epigenetic modifications on the NFATC1 gene were investigated by chromatin immunoprecipitation assays. RESULTS: NFATC1 was rapidly and transiently induced in early adaptation to acinar cell injury in human samples and in mice, where it promoted acinar cell transdifferentiation and blocked proliferation of metaplastic pancreatic cells. However, in late stages of regeneration, Nfatc1 was epigenetically silenced by EZH2-dependent histone methylation, to enable acinar cell redifferentiation and prevent organ atrophy and exocrine insufficiency. In contrast, oncogenic activation of KRAS signaling in pancreatic ductal adenocarcinoma cells reversed the EZH2-dependent effects on the NFATC1 gene and was required for EZH2-mediated transcriptional activation of NFATC1. CONCLUSIONS: In studies of human and mouse pancreatic cells and tissue, we identified context-specific epigenetic regulation of NFATc1 activity as an important mechanism of pancreatic cell plasticity. Inhibitors of EZH2 might therefore interfere with oncogenic activity of NFATC1 and be used in treatment of pancreatic ductal adenocarcinoma.
BACKGROUND & AIMS: The ability of exocrine pancreatic cells to change the cellular phenotype is required for tissue regeneration upon injury, but also contributes to their malignant transformation and tumor progression. We investigated context-dependent signaling and transcription mechanisms that determine pancreatic cell fate decisions toward regeneration and malignancy. In particular, we studied the function and regulation of the inflammatory transcription factor nuclear factor of activated T cells 1 (NFATC1) in pancreatic cell plasticity and tissue adaptation. METHODS: We analyzed cell plasticity during pancreatic regeneration and transformation in mice with pancreas-specific expression of a constitutively active form of NFATC1, or depletion of enhancer of zeste 2 homologue 2 (EZH2), in the context of wild-type or constitutively activate Kras, respectively. Acute and chronic pancreatitis were induced by intraperitoneal injection of caerulein. EZH2-dependent regulation of NFATC1 expression was studied in mouse in humanpancreatic tissue and cells by immunohistochemistry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. We used genetic and pharmacologic approaches of EZH2 and NFATC1 inhibition to study the consequences of pathway disruption on pancreatic morphology and function. Epigenetic modifications on the NFATC1 gene were investigated by chromatin immunoprecipitation assays. RESULTS:NFATC1 was rapidly and transiently induced in early adaptation to acinar cell injury in human samples and in mice, where it promoted acinar cell transdifferentiation and blocked proliferation of metaplastic pancreatic cells. However, in late stages of regeneration, Nfatc1 was epigenetically silenced by EZH2-dependent histone methylation, to enable acinar cell redifferentiation and prevent organ atrophy and exocrine insufficiency. In contrast, oncogenic activation of KRAS signaling in pancreatic ductal adenocarcinoma cells reversed the EZH2-dependent effects on the NFATC1 gene and was required for EZH2-mediated transcriptional activation of NFATC1. CONCLUSIONS: In studies of human and mousepancreatic cells and tissue, we identified context-specific epigenetic regulation of NFATc1 activity as an important mechanism of pancreatic cell plasticity. Inhibitors of EZH2 might therefore interfere with oncogenic activity of NFATC1 and be used in treatment of pancreatic ductal adenocarcinoma.
Authors: Tobias Raphael Overbeck; Dana Alina Cron; Katja Schmitz; Achim Rittmeyer; Wolfgang Körber; Sara Hugo; Juliane Schnalke; Laura Lukat; Tabea Hugo; Marc Hinterthaner; Kirsten Reuter-Jessen; Tessa Rosenthal; Joachim Moecks; Annalen Bleckmann; Hans-Ulrich Schildhaus Journal: Transl Lung Cancer Res Date: 2020-06
Authors: Ana P Kutschat; Feda H Hamdan; Xin Wang; Alexander Q Wixom; Zeynab Najafova; Christine S Gibhardt; Waltraut Kopp; Jochen Gaedcke; Philipp Ströbel; Volker Ellenrieder; Ivan Bogeski; Elisabeth Hessmann; Steven A Johnsen Journal: Cancer Res Date: 2021-01-12 Impact factor: 13.312