Heßmann, Elisabeth

[["dc.bibliographiccitation.firstpage","1470"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","Leukemia"],["dc.bibliographiccitation.lastpage","1477"],["dc.bibliographiccitation.volume","29"],["dc.contributor.author","Metzelder, S. K."],["dc.contributor.author","Michel, C."],["dc.contributor.author","von Bonin, Malte"],["dc.contributor.author","Rehberger, M."],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Inselmann, S."],["dc.contributor.author","Solovey, M."],["dc.contributor.author","Wang, Y."],["dc.contributor.author","Sohlbach, K."],["dc.contributor.author","Brendel, Cornelia"],["dc.contributor.author","Stiewe, Thorsten"],["dc.contributor.author","Charles, J."],["dc.contributor.author","Ten Haaf, A."],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Neubauer, A."],["dc.contributor.author","Gattenloehner, Stefan"],["dc.contributor.author","Bornhaeuser, Martin"],["dc.contributor.author","Burchert, Andreas"],["dc.date.accessioned","2018-11-07T09:55:10Z"],["dc.date.available","2018-11-07T09:55:10Z"],["dc.date.issued","2015"],["dc.description.abstract","Internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) are associated with a dismal prognosis in acute myeloid leukemia (AML). FLT3 inhibitors such as sorafenib may improve outcome, but only few patients display long-term responses, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them. Here we identified that the nuclear factor of activated T cells, NFATc1, is frequently overexpressed in FLT3-ITD-positive (FLT3-ITD+) AML. NFATc1 knockdown using inducible short hairpin RNA or pharmacological NFAT inhibition with cyclosporine A (CsA) or VIVIT significantly augmented sorafenib-induced apoptosis of FLT3-ITD+ cells. CsA also potently overcame sorafenib resistance in FLT3-ITD+ cell lines and primary AML. Vice versa, de novo expression of a constitutively nuclear NFATc1-mutant mediated instant and robust sorafenib resistance in vitro. Intriguingly, FLT3-ITD+ AML patients (n = 26) who received CsA as part of their rescue chemotherapy displayed a superior outcome when compared with wild-type FLT3 (FLT3-WT) AML patients. Our data unveil NFATc1 as a novel mediator of sorafenib resistance in FLT3-ITD+ AML. CsA counteracts sorafenib resistance and may improve treatment outcome in AML by means of inhibiting NFAT."],["dc.identifier.doi","10.1038/leu.2015.95"],["dc.identifier.isi","000357623100006"],["dc.identifier.pmid","25976987"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36691"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","1476-5551"],["dc.relation.issn","0887-6924"],["dc.title","NFATc1 as a therapeutic target in FLT3-ITD-positive AML"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","7677"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Russell, Ronan"],["dc.contributor.author","Perkhofer, Lukas"],["dc.contributor.author","Liebau, Stefan"],["dc.contributor.author","Lin, Qiong"],["dc.contributor.author","Lechel, Andre"],["dc.contributor.author","Feld, Fenja M."],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Guethle, Melanie"],["dc.contributor.author","Zenke, Martin"],["dc.contributor.author","Hartmann, Daniel"],["dc.contributor.author","von Figura, Guido"],["dc.contributor.author","Weissinger, Stephanie E."],["dc.contributor.author","Rudolph, K. Lenhard"],["dc.contributor.author","Moeller, Peter"],["dc.contributor.author","Lennerz, Jochen K."],["dc.contributor.author","Seufferlein, Thomas"],["dc.contributor.author","Wagner, Martin"],["dc.contributor.author","Kleger, Alexander"],["dc.date.accessioned","2018-11-07T09:54:59Z"],["dc.date.available","2018-11-07T09:54:59Z"],["dc.date.issued","2015"],["dc.description.abstract","Pancreatic ductal adenocarcinoma (PDAC) is associated with accumulation of particular oncogenic mutations and recent genetic sequencing studies have identified ataxia telangiectasia-mutated (ATM) mutations in PDAC cohorts. Here we report that conditional deletion of ATM in a mouse model of PDAC induces a greater number of proliferative precursor lesions coupled with a pronounced fibrotic reaction. ATM-targeted mice display altered TGF beta-superfamily signalling and enhanced epithelial-to-mesenchymal transition (EMT) coupled with shortened survival. Notably, our mouse model recapitulates many features of more aggressive human PDAC subtypes. Particularly, we report that low expression of ATM predicts EMT, a gene signature specific for Bmp4 signalling and poor prognosis in human PDAC. Our data suggest an intimate link between ATM expression and pancreatic cancer progression in mice and men."],["dc.identifier.doi","10.1038/ncomms8677"],["dc.identifier.isi","000358858100021"],["dc.identifier.pmid","26220524"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12073"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36658"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2041-1723"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","eLife"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Zhang, Zhe"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.date.accessioned","2020-12-10T18:48:06Z"],["dc.date.available","2020-12-10T18:48:06Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.7554/eLife.38967"],["dc.identifier.eissn","2050-084X"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/79019"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","To be or not to be"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","446"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Cell Death & Disease"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Hasselluhn, Marie C."],["dc.contributor.author","Schmidt, Geske E."],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Johnsen, Steven A."],["dc.contributor.author","Hessmann, Elisabeth"],["dc.date.accessioned","2021-04-26T11:54:12Z"],["dc.date.available","2021-04-26T11:54:12Z"],["dc.date.issued","2019"],["dc.description.abstract","Given its aggressive tumor biology and its exceptional therapy resistance, pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <8%. At the cellular level, PDAC is largely driven by the activation of signaling pathways that eventually converge in altered, tumor-promoting transcription programs. In this study, we sought to determine the interplay between transforming growth factor β (TGFβ) signaling and activation of the inflammatory transcription factor nuclear factor of activated T cells (NFATc1) in the regulation of transcriptional programs throughout PDAC progression. Genome-wide transcriptome analysis and functional studies performed in primary PDAC cells and transgenic mice linked nuclear NFATc1 expression with pro-proliferative and anti-apoptotic gene signatures. Consistently, NFATc1 depletion resulted in downregulation of target genes associated with poor PDAC outcome and delayed pancreatic carcinogenesis in vivo. In contrast to previous reports and consistent with a concept of retained tumor suppressive TGFβ activity, even in established PDAC, TGFβ treatment reduced PDAC cell proliferation and promoted apoptosis even in the presence of oncogenic NFATc1. However, combined TGFβ treatment and NFATc1 depletion resulted in a tremendous abrogation of tumor-promoting gene signatures and functions. Chromatin studies implied that TGFβ-dependent regulators compete with NFATc1 for the transcriptional control of jointly regulated target genes associated with an unfavorable PDAC prognosis. Together, our findings suggest opposing consequences of TGFβ and NFATc1 activity in the regulation of pro-tumorigenic transcription programs in PDAC and emphasize the strong context-dependency of key transcription programs in the progression of this devastating disease."],["dc.identifier.doi","10.1038/s41419-019-1682-2"],["dc.identifier.pmid","31171768"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16449"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/84359"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Aberrant NFATc1 signaling counteracts TGFβ-mediated growth arrest and apoptosis induction in pancreatic cancer progression"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["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","484"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","EBioMedicine"],["dc.bibliographiccitation.lastpage","485"],["dc.bibliographiccitation.volume","2"],["dc.contributor.author","Neesse, A."],["dc.contributor.author","Hessmann, E."],["dc.date.accessioned","2021-04-26T11:54:21Z"],["dc.date.available","2021-04-26T11:54:21Z"],["dc.date.issued","2015-06"],["dc.identifier.doi","10.1016/j.ebiom.2015.05.017"],["dc.identifier.pmid","26288808"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/84361"],["dc.language.iso","en"],["dc.relation.issn","2352-3964"],["dc.title","Electron Transfer-Based Compounds: A Novel Weapon in the Cancer Battlespace?"],["dc.type","journal_article"],["dc.type.internalPublication","no"],["dc.type.subtype","original_ja"],["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.artnumber","canres.2874.2020"],["dc.bibliographiccitation.journal","Cancer Research"],["dc.contributor.author","Kutschat, Ana P."],["dc.contributor.author","Hamdan, Feda H."],["dc.contributor.author","Wang, Xin"],["dc.contributor.author","Wixom, Alexander Q."],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Gibhardt, Christine S."],["dc.contributor.author","Kopp, Waltraut"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Ströbel, Philipp"],["dc.contributor.author","Ellenrieder, Volker"],["dc.contributor.author","Bogeski, Ivan"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2021-04-26T11:54:17Z"],["dc.date.available","2021-04-26T11:54:17Z"],["dc.date.issued","2021-01-12"],["dc.description.abstract","Pancreatic Ductal Adenocarcinoma (PDAC) displays a dismal prognosis due to late diagnosis and high chemoresistance incidence. For advanced disease stages or patients with comorbidities, treatment options are limited to gemcitabine alone or in combination with other drugs. While gemcitabine resistance has been widely attributed to the levels of one of its targets, RRM1, the molecular consequences of gemcitabine resistance in PDAC remain largely elusive. Here we sought to identify genomic, epigenomic, and transcriptomic events associated with gemcitabine resistance in PDAC and their potential clinical relevance. We found that gemcitabine-resistant cells displayed a co-amplification of the adjacent RRM1 and STIM1 genes. Interestingly, RRM1, but not STIM1, was required for gemcitabine resistance, while high STIM1 levels caused an increase in cytosolic calcium concentration. Higher STIM1-dependent calcium influx led to an impaired ER stress response and a heightened NFAT activity. Importantly, these findings were confirmed in patient and patient-derived xenograft samples. Taken together, our study uncovers previously unknown biologically relevant molecular properties of gemcitabine-resistant tumors, revealing an undescribed function of STIM1 as a rheostat directing the effects of calcium signaling and controlling epigenetic cell fate determination. It further reveals the potential benefit of targeting STIM1-controlled calcium signaling and its downstream effectors in PDAC."],["dc.identifier.doi","10.1158/0008-5472.CAN-20-2874"],["dc.identifier.pmid","33436389"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/84360"],["dc.language.iso","en"],["dc.relation.eissn","1538-7445"],["dc.relation.issn","0008-5472"],["dc.title","STIM1 Mediates Calcium-dependent Epigenetic Reprogramming in Pancreatic Cancer"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","6334"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Nucleic Acids Research"],["dc.bibliographiccitation.lastpage","6349"],["dc.bibliographiccitation.volume","45"],["dc.contributor.author","Mishra, Vivek Kumar"],["dc.contributor.author","Wegwitz, Florian"],["dc.contributor.author","Kosinsky, Robyn Laura"],["dc.contributor.author","Sen, Madhobi"],["dc.contributor.author","Baumgartner, Roland"],["dc.contributor.author","Wulff, Tanja"],["dc.contributor.author","Siveke, Jens T."],["dc.contributor.author","Schildhaus, Hans-Ulrich"],["dc.contributor.author","Najafova, Zeynab"],["dc.contributor.author","Kari, Vijayalakshmi"],["dc.contributor.author","Kohlhof, Hella"],["dc.contributor.author","Hessmann, Elisabeth"],["dc.contributor.author","Johnsen, Steven A."],["dc.date.accessioned","2018-11-07T10:22:37Z"],["dc.date.available","2018-11-07T10:22:37Z"],["dc.date.issued","2017"],["dc.description.abstract","Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class Ispecific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGF beta signaling and inhibits TGF beta-induced epithelial-tomesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 (CDKN1A) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202-induced genes were enriched for Bromodomain-containing Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACi-mediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2017"],["dc.identifier.doi","10.1093/nar/gkx212"],["dc.identifier.isi","000403693000023"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14605"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42309"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","1362-4962"],["dc.relation.issn","0305-1048"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4-and MYC-dependent manner"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]