Heßmann, Elisabeth

[["dc.bibliographiccitation.firstpage","161"],["dc.bibliographiccitation.journal","EBioMedicine"],["dc.bibliographiccitation.lastpage","168"],["dc.bibliographiccitation.volume","48"],["dc.contributor.author","Ramu, Iswarya"],["dc.contributor.author","Buchholz, Sören M."],["dc.contributor.author","Patzak, Melanie S."],["dc.contributor.author","Goetze, Robert G."],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Richards, Frances M."],["dc.contributor.author","Jodrell, Duncan I."],["dc.contributor.author","Sipos, Bence"],["dc.contributor.author","Ströbel, Philipp"],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Neesse, Albrecht"],["dc.date.accessioned","2020-12-10T14:23:31Z"],["dc.date.available","2020-12-10T14:23:31Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1016/j.ebiom.2019.09.024"],["dc.identifier.issn","2352-3964"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16852"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/71949"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.title","SPARC dependent collagen deposition and gemcitabine delivery in a genetically engineered mouse model of pancreas cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1978"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Cancers"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Buchholz, Soeren M."],["dc.contributor.author","Goetze, Robert G."],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Ammer-Herrmenau, Christoph"],["dc.contributor.author","Richards, Frances M."],["dc.contributor.author","Jodrell, Duncan I."],["dc.contributor.author","Buchholz, Malte"],["dc.contributor.author","Michl, Patrick"],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Neesse, Albrecht"],["dc.date.accessioned","2021-04-14T08:25:07Z"],["dc.date.available","2021-04-14T08:25:07Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.3390/cancers12071978"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17498"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81527"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.notes.intern","Merged from goescholar"],["dc.relation.eissn","2072-6694"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Depletion of Macrophages Improves Therapeutic Response to Gemcitabine in Murine Pancreas Cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2561"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Gut"],["dc.bibliographiccitation.lastpage","2573"],["dc.bibliographiccitation.volume","71"],["dc.contributor.affiliation","Latif, Muhammad Umair; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Schmidt, Geske Elisabeth; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Mercan, Sercan; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Rahman, Raza; \r\n2\r\nGastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA"],["dc.contributor.affiliation","Gibhardt, Christine Silvia; \r\n3\r\nMolecular Physiology, Institute of Cardiovascular Physiology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Stejerean-Todoran, Ioana; \r\n3\r\nMolecular Physiology, Institute of Cardiovascular Physiology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Reutlinger, Kristina; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Hessmann, Elisabeth; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Singh, Shiv K; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Moeed, Abdul; \r\n4\r\nInstitute for Microbiology and Hygiene, Medical Center-University of Freiburg, Freiburg, Baden-Württemberg, Germany"],["dc.contributor.affiliation","Rehman, Abdul; \r\n5\r\nInstitute of Pharmacology and Toxicology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Butt, Umer Javed; \r\n6\r\nClinical Neuroscience, Max-Planck-Institute for Experimental Medicine, Goettingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Bohnenberger, Hanibal; \r\n7\r\nInstitute of Pathology, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.affiliation","Stroebel, Philipp; \r\n7\r\nInstitute of Pathology, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.affiliation","Bremer, Sebastian Christopher; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Neesse, Albrecht; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Bogeski, Ivan; \r\n3\r\nMolecular Physiology, Institute of Cardiovascular Physiology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.affiliation","Ellenrieder, Volker; \r\n1\r\nDepartment of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Niedersachsen, Germany"],["dc.contributor.author","Latif, Muhammad Umair"],["dc.contributor.author","Schmidt, Geske Elisabeth"],["dc.contributor.author","Mercan, Sercan"],["dc.contributor.author","Rahman, Raza"],["dc.contributor.author","Gibhardt, Christine Silvia"],["dc.contributor.author","Stejerean-Todoran, Ioana"],["dc.contributor.author","Reutlinger, Kristina"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Moeed, Abdul"],["dc.contributor.author","Rehman, Abdul"],["dc.contributor.author","Butt, Umer Javed"],["dc.contributor.author","Bohnenberger, Hanibal"],["dc.contributor.author","Stroebel, Philipp"],["dc.contributor.author","Bremer, Sebastian Christopher"],["dc.contributor.author","Neesse, Albrecht"],["dc.contributor.author","Bogeski, Ivan"],["dc.contributor.author","Ellenrieder, Volker"],["dc.date.accessioned","2022-12-07T08:25:00Z"],["dc.date.available","2022-12-07T08:25:00Z"],["dc.date.issued","2022-04-01"],["dc.date.updated","2022-12-07T00:46:04Z"],["dc.description.abstract","ObjectivesNon-alcoholic fatty liver disease (NAFLD) can persist in the stage of simple hepatic steatosis or progress to steatohepatitis (NASH) with an increased risk for cirrhosis and cancer. We examined the mechanisms controlling the progression to severe NASH in order to develop future treatment strategies for this disease.DesignNFATc1 activation and regulation was examined in livers from patients with NAFLD, cultured and primary hepatocytes and in transgenic mice with differential hepatocyte-specific expression of the transcription factor (Alb-cre, NFATc1c.a\r\n. and NFATc1Δ/Δ\r\n). Animals were fed with high-fat western diet (WD) alone or in combination with tauroursodeoxycholic acid (TUDCA), a candidate drug for NAFLD treatment. NFATc1-dependent ER stress-responses, NLRP3 inflammasome activation and disease progression were assessed both in vitro and in vivo.ResultsNFATc1 expression was weak in healthy livers but strongly induced in advanced NAFLD stages, where it correlates with liver enzyme values as well as hepatic inflammation and fibrosis. Moreover, high-fat WD increased NFATc1 expression, nuclear localisation and activation to promote NAFLD progression, whereas hepatocyte-specific depletion of the transcription factor can prevent mice from disease acceleration. Mechanistically, NFATc1 drives liver cell damage and inflammation through ER stress sensing and activation of the PERK-CHOP unfolded protein response (UPR). Finally, NFATc1-induced disease progression towards NASH can be blocked by TUDCA administration.ConclusionNFATc1 stimulates NAFLD progression through chronic ER stress sensing and subsequent activation of terminal UPR signalling in hepatocytes. Interfering with ER stress-responses, for example, by TUDCA, protects fatty livers from progression towards manifest NASH."],["dc.description.sponsorship","the Volkswagen-Stiftung"],["dc.description.sponsorship","http://dx.doi.org/10.13039/501100001659Deutsche Forschungsgemeinschaft"],["dc.description.sponsorship","German Cancer Aid"],["dc.identifier","35365570"],["dc.identifier.doi","10.1136/gutjnl-2021-325013"],["dc.identifier.pmid","35365570"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/118455"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/173"],["dc.language.iso","en"],["dc.publisher","BMJ Publishing Group Ltd and British Society of Gastroenterology"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","SFB 1190 | P17: Die Rolle mitochondrialer Kontaktstellen im Rahmen tumorrelevanter Calcium- und Redox-Signalwege"],["dc.relation.eissn","1468-3288"],["dc.relation.issn","0017-5749"],["dc.relation.workinggroup","RG Bogeski"],["dc.rights","CC BY-NC 4.0"],["dc.rights.uri","http://creativecommons.org/licenses/by-nc/4.0/"],["dc.title","NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","688"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Cancer Discovery"],["dc.bibliographiccitation.lastpage","701"],["dc.bibliographiccitation.volume","4"],["dc.contributor.author","Baumgart, Sandra"],["dc.contributor.author","Chen, Nai-Ming"],["dc.contributor.author","Siveke, Jens T."],["dc.contributor.author","Koenig, Alexander O."],["dc.contributor.author","Zhang, J."],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Wolf, Elmar"],["dc.contributor.author","Bartkuhn, Marek"],["dc.contributor.author","Esposito, Irene"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Reinecke, Johanna"],["dc.contributor.author","Nikorowitsch, Julius"],["dc.contributor.author","Brunner, Marius"],["dc.contributor.author","Singh, Garima"],["dc.contributor.author","Fernandez-Zapico, Martin E."],["dc.contributor.author","Smyrk, Thomas C."],["dc.contributor.author","Bamlet, William R."],["dc.contributor.author","Eilers, Martin"],["dc.contributor.author","Neesse, Albrecht"],["dc.contributor.author","Gress, Thomas M."],["dc.contributor.author","Billadeau, Daniel D."],["dc.contributor.author","Tuveson, David A."],["dc.contributor.author","Urrutia, Raul"],["dc.contributor.author","Ellenrieder, Volker"],["dc.date.accessioned","2018-11-07T09:39:31Z"],["dc.date.available","2018-11-07T09:39:31Z"],["dc.date.issued","2014"],["dc.description.abstract","Cancer-associated inflammation is a molecular key feature in pancreatic ductal adenocarcinoma. Oncogenic KRAS in conjunction with persistent inflammation is known to accelerate carcinogenesis, although the underlying mechanisms remain poorly understood. Here, we outline a novel pathway whereby the transcription factors NFATc1 and STAT3 cooperate in pancreatic epithelial cells to promote Kras(G12D) -driven carcinogenesis. NFATc1 activation is induced by inflammation and itself accelerates inflammation-induced carcinogenesis in Kras(G12D) mice, whereas genetic or pharmacologic ablation of NFATc1 attenuates this effect. Mechanistically, NFATc1 complexes with STAT3 for enhancer-promoter communications at jointly regulated genes involved in oncogenesis, for example, Cyclin, EGFR and WNT family members. The NFATc1-STAT3 cooperativity is operative in pancreatitis-mediated carcinogenesis as well as in established human pancreatic cancer. Together, these studies unravel new mechanisms of inflammatory-driven pancreatic carcinogenesis and suggest beneficial effects of chemopreventive strategies using drugs that are currently available for targeting these factors in clinical trials. SIGNIFICANCE: Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1STAT3 nucleoprotein complexes control the expression of gene networks at the intersection of inflammation and cancer, our study has significant relevance for potentially managing pancreatic cancer and other inflammatory-driven malignancies. (C) 2014 AACR."],["dc.identifier.doi","10.1158/2159-8290.CD-13-0593"],["dc.identifier.isi","000337185500025"],["dc.identifier.pmid","24694735"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/33304"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Assoc Cancer Research"],["dc.relation.issn","2159-8290"],["dc.relation.issn","2159-8274"],["dc.title","Inflammation-Induced NFATc1-STAT3 Transcription Complex Promotes Pancreatic Cancer Initiation by Kras(G12D)"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","14"],["dc.bibliographiccitation.journal","Cancers"],["dc.bibliographiccitation.volume","14"],["dc.contributor.affiliation","Versemann, Lennart; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.affiliation","Patil, Shilpa; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.affiliation","Steuber, Benjamin; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.affiliation","Zhang, Zhe; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.affiliation","Kopp, Waltraut; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.affiliation","Krawczyk, Hannah Elisa; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; elisa.krawczyk@outlook.de (H.E.K.); silke.kaulfuss@med.uni-goettingen.de (S.K.); bernd.wollnik@med.uni-goettingen.de (B.W.); philipp.stroebel@med.uni-goettingen.de (P.S.)"],["dc.contributor.affiliation","Kaulfuß, Silke; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; elisa.krawczyk@outlook.de (H.E.K.); silke.kaulfuss@med.uni-goettingen.de (S.K.); bernd.wollnik@med.uni-goettingen.de (B.W.); philipp.stroebel@med.uni-goettingen.de (P.S.)"],["dc.contributor.affiliation","Wollnik, Bernd; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; elisa.krawczyk@outlook.de (H.E.K.); silke.kaulfuss@med.uni-goettingen.de (S.K.); bernd.wollnik@med.uni-goettingen.de (B.W.); philipp.stroebel@med.uni-goettingen.de (P.S.)"],["dc.contributor.affiliation","Ströbel, Philipp; 2Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, 37075 Göttingen, Germany; elisa.krawczyk@outlook.de (H.E.K.); silke.kaulfuss@med.uni-goettingen.de (S.K.); bernd.wollnik@med.uni-goettingen.de (B.W.); philipp.stroebel@med.uni-goettingen.de (P.S.)"],["dc.contributor.affiliation","Neesse, Albrecht; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.affiliation","Singh, Shiv K.; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.affiliation","Ellenrieder, Volker; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.affiliation","Hessmann, Elisabeth; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; lennart.versemann@t-online.de (L.V.); shilpapatil528@gmail.com (S.P.); benjamin.steuber@med.uni-goettingen.de (B.S.); zhe.zhang@med.uni-goettingen.de (Z.Z.); wkopp@med.uni-goettingen.de (W.K.); albrecht.neesse@med.uni-goettingen.de (A.N.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.)"],["dc.contributor.author","Versemann, Lennart"],["dc.contributor.author","Patil, Shilpa"],["dc.contributor.author","Steuber, Benjamin"],["dc.contributor.author","Zhang, Zhe"],["dc.contributor.author","Kopp, Waltraut"],["dc.contributor.author","Krawczyk, Hannah Elisa"],["dc.contributor.author","Kaulfuß, Silke"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Ströbel, Philipp"],["dc.contributor.author","Neesse, Albrecht"],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.date.accessioned","2022-08-04T08:34:43Z"],["dc.date.available","2022-08-04T08:34:43Z"],["dc.date.issued","2022-07-15"],["dc.date.updated","2022-08-03T11:58:42Z"],["dc.description.abstract","Epigenetic alterations contribute to the aggressiveness and therapy resistance of Pancreatic Ductal Adenocarcinoma (PDAC). However, epigenetic regulators, including Enhancer of Zeste Homolog 2 (EZH2), reveal a strong context-dependent activity. Our study aimed to examine the context-defining molecular prerequisites of oncogenic EZH2 activity in PDAC to assess the therapeutic efficacy of targeting EZH2. Our preclinical study using diverse PDAC models demonstrates that the TP53 status determines oncogenic EZH2 activity. Only in TP53-wildtype (wt) PDAC subtypes was EZH2 blockade associated with a favorable PDAC prognosis mainly through cell-death response. We revealed that EZH2 depletion increases p53wt stability by the de-repression of CDKN2A. Therefore, our study provides preclinical evidence that an intact CDKN2A-p53wt axis is indispensable for a beneficial outcome of EZH2 depletion and highlights the significance of molecular stratification to improve epigenetic targeting in PDAC. \r\n \r\n \r\n Abstract\r\n Pancreatic Ductal Adenocarcinoma (PDAC) represents a lethal malignancy with a consistently poor outcome. Besides mutations in PDAC driver genes, the aggressive tumor biology of the disease and its remarkable therapy resistance are predominantly installed by potentially reversible epigenetic dysregulation. However, epigenetic regulators act in a context-dependent manner with opposing implication on tumor progression, thus critically determining the therapeutic efficacy of epigenetic targeting. Herein, we aimed at exploring the molecular prerequisites and underlying mechanisms of oncogenic Enhancer of Zeste Homolog 2 (EZH2) activity in PDAC progression. Preclinical studies in EZH2 proficient and deficient transgenic and orthotopic in vivo PDAC models and transcriptome analysis identified the TP53 status as a pivotal context-defining molecular cue determining oncogenic EZH2 activity in PDAC. Importantly, the induction of pro-apoptotic gene signatures and processes as well as a favorable PDAC prognosis upon EZH2 depletion were restricted to p53 wildtype (wt) PDAC subtypes. Mechanistically, we illustrate that EZH2 blockade de-represses CDKN2A transcription for the subsequent posttranslational stabilization of p53wt expression and function. Together, our findings suggest an intact CDKN2A-p53wt axis as a prerequisite for the anti-tumorigenic consequences of EZH2 depletion and emphasize the significance of molecular stratification for the successful implementation of epigenetic targeting in PDAC."],["dc.description.sponsorship","Wilhelm-Sander Stiftung"],["dc.description.sponsorship","German Cancer Aid"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft"],["dc.description.sponsorship","Ministry for Science and Culture in Lower Saxony/Volkswagenstiftung"],["dc.description.sponsorship","China Scholarship Council"],["dc.identifier.doi","10.3390/cancers14143451"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112631"],["dc.language.iso","en"],["dc.relation.eissn","2072-6694"],["dc.rights","CC BY 4.0"],["dc.title","TP53-Status-Dependent Oncogenic EZH2 Activity in Pancreatic Cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","497"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Gut"],["dc.bibliographiccitation.lastpage","507"],["dc.bibliographiccitation.volume","67"],["dc.contributor.author","Hessmann, E."],["dc.contributor.author","Patzak, M S"],["dc.contributor.author","Klein, L"],["dc.contributor.author","Chen, N"],["dc.contributor.author","Kari, V"],["dc.contributor.author","Ramu, I"],["dc.contributor.author","Bapiro, T E"],["dc.contributor.author","Frese, K K"],["dc.contributor.author","Gopinathan, A"],["dc.contributor.author","Richards, F M"],["dc.contributor.author","Jodrell, D I"],["dc.contributor.author","Verbeke, C"],["dc.contributor.author","Li, X"],["dc.contributor.author","Heuchel, R"],["dc.contributor.author","Löhr, J M"],["dc.contributor.author","Johnsen, S A"],["dc.contributor.author","Gress, T M"],["dc.contributor.author","Ellenrieder, V"],["dc.contributor.author","Neesse, A"],["dc.date.accessioned","2020-12-10T18:37:14Z"],["dc.date.available","2020-12-10T18:37:14Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1136/gutjnl-2016-311954"],["dc.identifier.eissn","1468-3288"],["dc.identifier.issn","0017-5749"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/76887"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","491"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Molecular Cancer Therapeutics"],["dc.bibliographiccitation.lastpage","502"],["dc.bibliographiccitation.volume","15"],["dc.contributor.author","Zhang, L."],["dc.contributor.author","Baumgart, Sandra"],["dc.contributor.author","Chen, Nai-Ming"],["dc.contributor.author","Zhang, J."],["dc.contributor.author","Billadeau, Daniel D."],["dc.contributor.author","Gaisina, Irina N."],["dc.contributor.author","Kozikowski, Alan P."],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Fink, Daniel"],["dc.contributor.author","Ströbel, Philipp"],["dc.contributor.author","Klindt, Caroline"],["dc.contributor.author","Bamlet, William R."],["dc.contributor.author","König, Alexander O."],["dc.contributor.author","Heßmann, Elisabeth"],["dc.contributor.author","Gress, Thomas M."],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Neeße, Albrecht"],["dc.date.accessioned","2020-12-10T18:37:46Z"],["dc.date.available","2020-12-10T18:37:46Z"],["dc.date.issued","2016"],["dc.description.abstract","We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3 beta (GSK-3 beta) in the regulation and activation of the proinflammatory oncogenic transcription factor nuclear factor of activated T cells (NFATc2) in pancreatic cancer. IHC, qPCR, immunoblotting, immunofluorescence microscopy, and proliferation assays were used to analyze mouse and human tissues and cell lines. Protein-protein interactions and promoter regulation were analyzed by coimmunoprecipitation, DNA pulldown, reporter, and ChIP assays. Preclinical assays were performed using a variety of pancreatic cancer cells lines, xenografts, and a genetically engineered mouse model (GEMM). GSK-3 beta-dependent SP2 phosphorylationmediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3 beta also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3 beta-mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters, such as cyclin-dependent kinase-6, which promotes tumor growth. Finally, preclinical experiments suggest that targeting the NFATc2-STAT3-GSK-3b module inhibits proliferation and tumor growth and interferes with inflammation-induced pancreatic cancer progression in Kras(G12D) mice. In conclusion, we describe a novel mechanism by which GSK3 beta fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth. Furthermore, the therapeutic potential of GSK-3 beta is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer. (C) 2016 AACR."],["dc.identifier.doi","10.1158/1535-7163.MCT-15-0309"],["dc.identifier.eissn","1538-8514"],["dc.identifier.isi","000373595600015"],["dc.identifier.issn","1535-7163"],["dc.identifier.pmid","26823495"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77088"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Amer Assoc Cancer Research"],["dc.relation.issn","1538-8514"],["dc.relation.issn","1535-7163"],["dc.title","GSK-3 beta Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4620"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","Cancer Research"],["dc.bibliographiccitation.lastpage","4632"],["dc.bibliographiccitation.volume","80"],["dc.contributor.author","Patil, Shilpa"],["dc.contributor.author","Steuber, Benjamin"],["dc.contributor.author","Kopp, Waltraut"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Urbach, Laura"],["dc.contributor.author","Wang, Xin"],["dc.contributor.author","Küffer, Stefan"],["dc.contributor.author","Bohnenberger, Hanibal"],["dc.contributor.author","Spyropoulou, Dimitra"],["dc.contributor.author","Zhang, Zhe"],["dc.contributor.author","Versemann, Lennart"],["dc.contributor.author","Bösherz, Mark Sebastian"],["dc.contributor.author","Brunner, Marius"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Ströbel, Philipp"],["dc.contributor.author","Zhang, Jin-San"],["dc.contributor.author","Neesse, Albrecht"],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Hessmann, Elisabeth"],["dc.date.accessioned","2021-04-14T08:31:24Z"],["dc.date.available","2021-04-14T08:31:24Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1158/0008-5472.CAN-20-0672"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83584"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation.eissn","1538-7445"],["dc.relation.issn","0008-5472"],["dc.title","EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3463"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Cells"],["dc.bibliographiccitation.volume","10"],["dc.contributor.affiliation","Patil, Shilpa; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.affiliation","Forster, Teresa; 2Department of Gastroenterology, Endocrinology, Metabolism and Clinical Infectiology, Philipps University Marburg, 35043 Marburg, Germany; terry.forster@web.de"],["dc.contributor.affiliation","Reutlinger, Kristina; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.affiliation","Kopp, Waltraut; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.affiliation","Versemann, Lennart; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.affiliation","Spitalieri, Jessica; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.affiliation","Gaedcke, Jochen; 3Clinical Research Unit KFO5002, University Medical Center Goettingen, 37075 Goettingen, Germany; jochen.gaedcke@med.uni-goettingen.de (J.G.); philipp.stroebel@med.uni-goettingen.de (P.S.)"],["dc.contributor.affiliation","Ströbel, Philipp; 3Clinical Research Unit KFO5002, University Medical Center Goettingen, 37075 Goettingen, Germany; jochen.gaedcke@med.uni-goettingen.de (J.G.); philipp.stroebel@med.uni-goettingen.de (P.S.)"],["dc.contributor.affiliation","Singh, Shiv K.; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.affiliation","Ellenrieder, Volker; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.affiliation","Neesse, Albrecht; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.affiliation","Hessmann, Elisabeth; 1Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, 37075 Goettingen, Germany; shilpapatil528@gmail.com (S.P.); kristina.reutlinger@med.uni-goettingen.de (K.R.); wkopp@med.uni-goettingen.de (W.K.); lennart.versemann@t-online.de (L.V.); jspitali@med.uni-goettingen.de (J.S.); shiv.singh@med.uni-goettingen.de (S.K.S.); volker.ellenrieder@med.uni-goettingen.de (V.E.); albrecht.neesse@med.uni-goettingen.de (A.N.)"],["dc.contributor.author","Patil, Shilpa"],["dc.contributor.author","Forster, Teresa"],["dc.contributor.author","Reutlinger, Kristina"],["dc.contributor.author","Kopp, Waltraut"],["dc.contributor.author","Versemann, Lennart"],["dc.contributor.author","Spitalieri, Jessica"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Ströbel, Philipp"],["dc.contributor.author","Singh, Shiv K."],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Neesse, Albrecht"],["dc.contributor.editor","Cavestro, Giulia Martina"],["dc.date.accessioned","2022-01-11T14:08:09Z"],["dc.date.available","2022-01-11T14:08:09Z"],["dc.date.issued","2021"],["dc.date.updated","2022-02-09T13:20:00Z"],["dc.description.abstract","Background: The Nuclear Factor of Activated T-cells 1 (NFATc1) transcription factor and the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) significantly contribute to the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). Herein, we aimed at dissecting the mechanistic background of their interplay in PDAC progression. Methods: NFATc1 and EZH2 mRNA and protein expression and complex formation were determined in transgenic PDAC models and human PDAC specimens. NFATc1 binding on the Ezh2 gene and the consequences of perturbed NFATc1 expression on Ezh2 transcription were explored by Chromatin Immunoprecipitation (ChIP) and upon transgenic or siRNA-mediated interference with NFATc1 expression, respectively. Integrative analyses of RNA- and ChIP-seq data was performed to explore NFATc1-/EZH2-dependent gene signatures. Results: NFATc1 targets the Ezh2 gene for transcriptional activation and biochemically interacts with the methyltransferase in murine and human PDAC. Surprisingly, our genome-wide binding and expression analyses do not link the protein complex to joint gene regulation. In contrast, our findings provide evidence for chromatin-independent functions of the NFATc1:EZH2 complex and reveal posttranslational EZH2 phosphorylation at serine 21 as a prerequisite for robust complex formation. Conclusion: Our findings disclose a previously unknown NFATc1-EZH2 axis operational in the pancreas and provide mechanistic insights into the conditions fostering NFATc1:EZH2 complex formation in PDAC."],["dc.description.abstract","Background: The Nuclear Factor of Activated T-cells 1 (NFATc1) transcription factor and the methyltransferase Enhancer of Zeste Homolog 2 (EZH2) significantly contribute to the aggressive phenotype of pancreatic ductal adenocarcinoma (PDAC). Herein, we aimed at dissecting the mechanistic background of their interplay in PDAC progression. Methods: NFATc1 and EZH2 mRNA and protein expression and complex formation were determined in transgenic PDAC models and human PDAC specimens. NFATc1 binding on the Ezh2 gene and the consequences of perturbed NFATc1 expression on Ezh2 transcription were explored by Chromatin Immunoprecipitation (ChIP) and upon transgenic or siRNA-mediated interference with NFATc1 expression, respectively. Integrative analyses of RNA- and ChIP-seq data was performed to explore NFATc1-/EZH2-dependent gene signatures. Results: NFATc1 targets the Ezh2 gene for transcriptional activation and biochemically interacts with the methyltransferase in murine and human PDAC. Surprisingly, our genome-wide binding and expression analyses do not link the protein complex to joint gene regulation. In contrast, our findings provide evidence for chromatin-independent functions of the NFATc1:EZH2 complex and reveal posttranslational EZH2 phosphorylation at serine 21 as a prerequisite for robust complex formation. Conclusion: Our findings disclose a previously unknown NFATc1-EZH2 axis operational in the pancreas and provide mechanistic insights into the conditions fostering NFATc1:EZH2 complex formation in PDAC."],["dc.identifier.doi","10.3390/cells10123463"],["dc.identifier.eissn","2073-4409"],["dc.identifier.pii","cells10123463"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/97947"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-507"],["dc.publisher","MDPI"],["dc.relation.eissn","2073-4409"],["dc.rights","Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)."],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Chromatin-Independent Interplay of NFATc1 and EZH2 in Pancreatic Cancer"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1507"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Gastroenterology"],["dc.bibliographiccitation.lastpage","+"],["dc.bibliographiccitation.volume","152"],["dc.contributor.author","Chen, Nai-Ming"],["dc.contributor.author","Neeße, Albrecht"],["dc.contributor.author","Dyck, Moritz Lino"],["dc.contributor.author","Steuber, Benjamin"],["dc.contributor.author","König, Alexander Otto"],["dc.contributor.author","Lubeseder-Martellato, Clara"],["dc.contributor.author","Winter, Thore"],["dc.contributor.author","Forster, Teresa"],["dc.contributor.author","Bohnenberger, Hanibal"],["dc.contributor.author","Kitz, Julia"],["dc.contributor.author","Reuter-Jessen, Kirsten"],["dc.contributor.author","Griesmann, Heidi"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Grade, Marian"],["dc.contributor.author","Zhang, J."],["dc.contributor.author","Tsai, Wan-Chi"],["dc.contributor.author","Siveke, Jens T."],["dc.contributor.author","Schildhaus, Hans-Ulrich"],["dc.contributor.author","Ströbel, Philipp"],["dc.contributor.author","Johnsen, Steven Arthur"],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Heßmann, Elisabeth"],["dc.date.accessioned","2018-11-07T10:24:16Z"],["dc.date.available","2018-11-07T10:24:16Z"],["dc.date.issued","2017"],["dc.description.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 trans-differentiation 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."],["dc.identifier.doi","10.1053/j.gastro.2017.01.043"],["dc.identifier.isi","000401811300041"],["dc.identifier.pmid","28188746"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42625"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","W B Saunders Co-elsevier Inc"],["dc.relation.issn","1528-0012"],["dc.relation.issn","0016-5085"],["dc.title","Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]