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Pancreatic Neoplasms: HELP
Articles by Volker Ellenrieder
Based on 29 articles published since 2009
(Why 29 articles?)
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Between 2009 and 2019, V. Ellenrieder wrote the following 29 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Transcriptional control of gene expression in pancreatic cancer: from sequence-specific transcription factors to nuclear architecture. 2011

Ellenrieder, Volker / Fernandez-Zapico, Martin E. · ·J Gastrointest Cancer · Pubmed #21279553.

ABSTRACT: Transcription plays a central role in the regulation of gene expression during neoplastic transformation in different tissues. Using this nuclear process as a common topic in this special issue of the Journal of Gastrointestinal Cancer we have covered with five review articles key aspects of gene transcription and its impact in pancreatic carcinogenesis. We are confident that the knowledge included in these review articles will help understand the contribution of this molecular event to the pathogenesis of this devastating disease and serve as foundation for the development of new therapeutic tools.

2 Review Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? 2017

Hessmann, Elisabeth / Johnsen, Steven A / Siveke, Jens T / Ellenrieder, Volker. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. · Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany. · Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · West German Cancer Center, University Hospital Essen, Essen, Germany. ·Gut · Pubmed #27811314.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most aggressive malignancies with a 5-year survival rate of <7%. Due to growing incidence, late diagnosis and insufficient treatment options, PDAC is predicted to soon become one of the leading causes of cancer-related death. Although intensified cytostatic combinations, particularly gemcitabine plus nab-paclitaxel and the folinic acid, fluorouracil, irinotecan, oxaliplatin (FOLFIRINOX) protocol, provide some improvement in efficacy and survival compared with gemcitabine alone, a breakthrough in the treatment of metastatic pancreatic cancer remains out of sight. Nevertheless, recent translational research activities propose that either modulation of the immune response or pharmacological targeting of epigenetic modifications alone, or in combination with chemotherapy, might open highly powerful therapeutic avenues in GI cancer entities, including pancreatic cancer. Deregulation of key epigenetic factors and chromatin-modifying proteins, particularly those responsible for the addition, removal or recognition of post-translational histone modifications, are frequently found in human pancreatic cancer and hence constitute particularly exciting treatment opportunities. This review summarises both current clinical trial activities and discovery programmes initiated throughout the biopharma landscape, and critically discusses the chances, hurdles and limitations of epigenetic-based therapy in future PDAC treatment.

3 Review Current Standard and Future Perspectives in First- and Second-Line Treatment of Metastatic Pancreatic Adenocarcinoma. 2016

Ellenrieder, Volker / König, Alexander / Seufferlein, Thomas. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. ·Digestion · Pubmed #27438590.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a median 5-year survival of <8%. At the time of diagnosis, a vast majority of pancreatic cancer patients were found to be with either metastatic spread of the disease or locally advanced tumors. Despite relatively low efficacy, gemcitabine administration was the first choice chemotherapeutic strategy in advanced PDAC for many years. In the last 5 years, however, our understanding of pancreatic carcinogenesis has improved dramatically and with this our therapeutic options have expanded significantly. SUMMARY: With the FOLFIRINOX protocol or the combination of gemcitabine and nab-paclitaxel, 2 novel and more effective chemotherapeutic regimens have been introduced in clinical routine, which increased the overall survival by 4-5 months in the palliative situation. Most recently, we learned that both regimens can be modified and dosages can be adapted in older patients without significant loss of efficacy. Additionally, novel application strategies such as nanoparticle fused liposomal irinotecan along with 5-FU/LV provided convincing results in patients previously treated with gemcitabine. Current preclinical and clinical trials investigate efficacy and tolerability of novel drugs aiming at the inhibition of key inflammatory pathways, for example, JAK-STAT signaling, or the tumor surrounding desmoplasia. Prospectively, immunovaccination approaches or immune checkpoint inhibition appears as promising strategies in the near future, particularly when combined with epigenetic drugs in advanced PDAC patients. In this 'to-the-point' article, we review the current standard and summarize the most recent and encouraging advances in cytostatic PDAC treatment. KEY POINTS: (1) FOLFIRINOX and nab-paclitaxel/gemcitabine as first-line treatment regime significantly increase survival in patients with advanced PDAC; (2) Selection of appropriate treatment regime depends on patient performance, comorbidity, and toxicity; (3) PDAC patients will benefit from second-line chemotherapy and selection of appropriate regimes depends on first line therapy and patient criteria; (4) Future therapeutic strategies in advanced PDAC will respect molecular tumor profiling and other biomarkers.

4 Review MYC in pancreatic cancer: novel mechanistic insights and their translation into therapeutic strategies. 2016

Hessmann, E / Schneider, G / Ellenrieder, V / Siveke, J T. ·Clinic for Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. · Department of Internal Medicine II, Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Oncogene · Pubmed #26119937.

ABSTRACT: Owing to its aggressiveness, late detection and marginal therapeutic accessibility, pancreatic ductal adenocarcinoma (PDAC) remains a most challenging malignant disease. Despite scientific progress in the understanding of the mechanisms that underly PDAC initiation and progression, the successful translation of experimental findings into effective new therapeutic strategies remains a largely unmet need. The oncogene MYC is activated in many PDAC cases and is a master regulator of vital cellular processes. Excellent recent studies have shed new light on the tremendous functions of MYC in cancer and identified inhibition of MYC as a likewise beneficial and demanding effort. This review will focus on mechanisms that contribute to deregulation of MYC expression in pancreatic carcinogenesis and progression and will summarize novel biological findings from recent in vivo models. Finally, we provide a perspective, how regulation of MYC in PDAC may contribute to the development of new therapeutic approaches.

5 Review nab-Paclitaxel: novel clinical and experimental evidence in pancreatic cancer. 2014

Neesse, A / Michl, P / Tuveson, D A / Ellenrieder, V. ·Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps University Marburg, Marburg, Germany. · Cold Spring Harbor, Laboratory Cold Spring Harbor, NY, USA. ·Z Gastroenterol · Pubmed #24687799.

ABSTRACT: The past few decades have seen virtually no treatment advances for patients with metastatic pancreatic cancer. Clinical hallmark features of pancreatic ductal adenocarcinoma (PDA) include late symptom onset, invasive growth, early liver and lymph node metastasis, and resistance to available chemotherapies. nab-Paclitaxel (Abraxane®) is generated through high-pressure homogenization of human albumin and conventional paclitaxel resulting in non-covalently bound, water-soluble albumin-paclitaxel particles with an approximate diameter of 130 nm. Results from the recently completed Metastatic Pancreatic Adenocarcinoma Trial (MPACT) (phase III trial) showed a significant survival benefit for patients treated with nab-paclitaxel in combination with gemcitabine, and this treatment regimen is currently being implemented in national and international guidelines for PDA patients. Therefore, this regimen provides a much needed vantage point of attack for this recalcitrant tumor offering potential new hope for our patients. Mechanisms such as stromal depletion, selective intratumoral accumulation, synergism with gemcitabine metabolism and secreted protein acidic and rich in cysteine (SPARC) mediated anti-tumor activity have been suggested for nab-paclitaxel. This review discusses the clinical and experimental advances of nab-paclitaxel in pancreatic cancer.

6 Review Senescence in pancreatic carcinogenesis: from signalling to chromatin remodelling and epigenetics. 2013

Singh, Shiv K / Ellenrieder, Volker. ·Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University of Marburg, Marburg, Germany. ·Gut · Pubmed #23408353.

ABSTRACT: Mutational activation of K-Ras is a key genetic event involved in the initiation of pancreatic carcinogenesis. However, K-Ras generally fails to transform precursor lesions into invasive cancers due to activation of powerful fail-safe programmes that counteract transformation and growth. The importance of cellular senescence, a permanent cell growth arrest, is increasingly being recognised as a critical fail-safe programme in pancreatic carcinogenesis. Emerging evidence suggests that oncogene-induced senescence requires transcriptional induction of the CDKN2A gene locus as well as comprehensive chromatin modifications involved in epigenetic silencing of pro-proliferative genes. Moreover, recent work in pancreatic cancer mouse models proposes that inactivation of the CDKN2A tumour suppressor locus is the molecular switch required for senescence evasion and unleashed K-Ras driven malignant transformation in the pancreas.

7 Review Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis. 2013

McCleary-Wheeler, Angela L / Lomberk, Gwen A / Weiss, Frank U / Schneider, Günter / Fabbri, Muller / Poshusta, Tara L / Dusetti, Nelson J / Baumgart, Sandra / Iovanna, Juan L / Ellenrieder, Volker / Urrutia, Raul / Fernandez-Zapico, Martin E. ·Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Rochester, MN, USA. ·Cancer Lett · Pubmed #23073473.

ABSTRACT: During the last couple decades, we have significantly advanced our understanding of mechanisms underlying the development of pancreatic ductual adenocarcinoma (PDAC). In the late 1990s into the early 2000s, a model of PDAC development and progression was developed as a multi-step process associated with the accumulation of somatic mutations. The correlation and association of these particular genetic aberrations with the establishment and progression of PDAC has revolutionized our understanding of this process. However, this model leaves out other molecular events involved in PDAC pathogenesis that contribute to its development and maintenance, specifically those being epigenetic events. Thus, a new model considering the new scientific paradigms of epigenetics will provide a more comprehensive and useful framework for understanding the pathophysiological mechanisms underlying this disease. Epigenetics is defined as the type of inheritance not based on a particular DNA sequence but rather traits that are passed to the next generation via DNA and histone modifications as well as microRNA-dependent mechanisms. Key tumor suppressors that are well established to play a role in PDAC may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. A noteworthy characteristic of epigenetic-based inheritance is its reversibility, which is in contrast to the stable nature of DNA sequence-based alterations. Given this nature of epigenetic alterations, it becomes imperative that our understanding of epigenetic-based events promoting and maintaining PDAC continues to grow.

8 Review Oncogenic transcription factors: cornerstones of inflammation-linked pancreatic carcinogenesis. 2013

Baumgart, Sandra / Ellenrieder, Volker / Fernandez-Zapico, Martin E. ·Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps-University of Marburg, Marburg, Germany. ·Gut · Pubmed #21997559.

ABSTRACT: Transcription factors are proteins that regulate gene expression by modulating the synthesis of messenger RNA. Since this process is often one dominant control point in the production of many proteins, transcription factors represent the key regulators of numerous cellular functions, including proliferation, differentiation and apoptosis. Pancreatic cancer progression is characterised by activation of inflammatory signalling pathways converging on a limited set of transcription factors that fine-tune gene expression patterns contributing to the growth and maintenance of these tumours. Thus strategies targeting these transcriptional networks activated in pancreatic cancer cells could block the effects of upstream inflammatory responses participating in pancreatic tumorigenesis. The authors review this field of research and summarise current strategies for targeting oncogenic transcription factors and their activating signalling networks in the treatment of pancreatic cancer.

9 Review Inflammation, regeneration, and transformation in the pancreas: results of the Collaborative Research Center 518 (SFB 518) at the University of Ulm. 2011

Giehl, Klaudia / Bachem, Max / Beil, Michael / Böhm, Bernhard O / Ellenrieder, Volker / Fulda, Simone / Gress, Thomas M / Holzmann, Karlheinz / Kestler, Hans A / Kornmann, Marko / Menke, Andre / Möller, Peter / Oswald, Franz / Schmid, Roland M / Schmidt, Volker / Schirmbeck, Reinhold / Seufferlein, Thomas / von Wichert, Götz / Wagner, Martin / Walther, Paul / Wirth, Thomas / Adler, Guido. ·Department of Internal Medicine I, Center for Internal Medicine, University of Ulm, Germany. klaudia.giehl@innere.med.uni-giessen.de ·Pancreas · Pubmed #21483252.

ABSTRACT: The primary diseases of the pancreas include diabetes mellitus, acute and chronic pancreatitis, as well as pancreatic carcinoma. This review presents findings and emerging questions on the diseases of the pancreas obtained by the consortium of the Collaborative Research Center 518 (SFB 518), "Inflammation, Regeneration, and Transformation in the Pancreas" at the University of Ulm. During the last 12 years, the SFB 518 contributed considerably to the understanding of the cellular and molecular basis of pancreatic diseases and established the basis for the development of new strategies for prevention and causal therapy for diabetes, pancreatitis, and pancreatic cancer.

10 Review Primers on molecular pathways--the NFAT transcription pathway in pancreatic cancer. 2010

König, Alexander / Fernandez-Zapico, Martin E / Ellenrieder, Volker. ·Signal Transduction and Transcription Laboratory, Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany. ·Pancreatology · Pubmed #20720442.

ABSTRACT: The calcineurin-responsive nuclear factor of activated T cells (NFAT) family of transcription factors was originally identified as a group of inducible nuclear proteins, which regulate transcription during T lymphocyte activation. However, following their initial discovery, a multitude of studies quickly established that NFAT proteins are also expressed in cells outside the immune system, where they participate in the regulation of the expression of genes influencing cell growth and differentiation. Ectopic activation of individual NFAT members is now recognized as an important aspect for oncogenic transformation in several human malignancies, most notably in pancreatic cancer. Sustained activation of the Ca(2+)/calcineurin/NFAT signaling pathway has emerged as a powerful regulatory principle governing pancreatic cancer cell growth. Activated NFAT proteins form complexes with key oncogenic proteins to regulate the transcription of master cell cycle regulators and proteins with functions in cell survival, migration and angiogenesis. This review pays particular attention to recent advances in our understanding of how the NFAT transcription pathway controls gene expression during development and progression of pancreatic cancer. and IAP.

11 Article Cytosolic 5'-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites. 2019

Patzak, Melanie S / Kari, Vijayalakshmi / Patil, Shilpa / Hamdan, Feda H / Goetze, Robert G / Brunner, Marius / Gaedcke, Jochen / Kitz, Julia / Jodrell, Duncan I / Richards, Frances M / Pilarsky, Christian / Gruetzmann, Robert / Rümmele, Petra / Knösel, Thomas / Hessmann, Elisabeth / Ellenrieder, Volker / Johnsen, Steven A / Neesse, Albrecht. ·University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany. · University Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, Germany. · University Medical Center Goettingen, Institute of Pathology, Goettingen, Germany. · Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom. · University Medical Center Erlangen, Department of Surgery, Erlangen, Germany. · University Medical Center Erlangen, Institute of Pathology, Erlangen, Germany. · Ludwig Maximilian University Munich, Institute of Pathology, Munich, Germany. · University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany. Electronic address: albrecht.neesse@med.uni-goettingen.de. ·EBioMedicine · Pubmed #30709769.

ABSTRACT: BACKGROUND: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. METHODS: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). FINDINGS: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44-56% score 2 and 8-26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. INTERPRETATION: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC.

12 Article Utilizing High Resolution Ultrasound to Monitor Tumor Onset and Growth in Genetically Engineered Pancreatic Cancer Models. 2018

Goetze, Robert-Guenther / Buchholz, Soeren M / Patil, Shilpa / Petzold, Golo / Ellenrieder, Volker / Hessmann, Elisabeth / Neesse, Albrecht. ·Department Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen. · Department Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen; albrecht.neesse@med.uni-goettingen.de. ·J Vis Exp · Pubmed #29683461.

ABSTRACT: The LSL-Kras

13 Article Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer. 2018

Hessmann, E / Patzak, M S / Klein, L / Chen, N / Kari, V / Ramu, I / Bapiro, T E / Frese, K K / Gopinathan, A / Richards, F M / Jodrell, D I / Verbeke, C / Li, X / Heuchel, R / Löhr, J M / Johnsen, S A / Gress, T M / Ellenrieder, V / Neesse, A. ·Department Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Goettingen, Germany. · Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany. · Cancer Research UK Cambridge Institute, The University of Cambridge, Li Ka Shing Centre, Cambridge, UK. · Oncology iMED DMPK AstraZeneca UK Ltd, HODGKIN C/o B310 Cambridge Science Park, Cambridge, UK. · The University of Manchester, Cancer Research UK Manchester Institute, Manchester, UK. · Department of Oncology, University of Cambridge, Cambridge, UK. · Department of Pathology, Karolinska University Hospital, Stockholm, Sweden. · Department of Pathology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden. · Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Marburg, Germany. ·Gut · Pubmed #28077438.

ABSTRACT: OBJECTIVE: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery. DESIGN: Gemcitabine metabolites were analysed in RESULTS: Gemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2',2'-difluorodeoxycytidine-5'-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2',2'-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5'-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%. CONCLUSIONS: Our findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.

14 Article Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity. 2017

Chen, Nai-Ming / Neesse, Albrecht / Dyck, Moritz Lino / Steuber, Benjamin / Koenig, Alexander O / Lubeseder-Martellato, Clara / Winter, Thore / Forster, Teresa / Bohnenberger, Hanibal / Kitz, Julia / Reuter-Jessen, Kirsten / Griesmann, Heidi / Gaedcke, Jochen / Grade, Marian / Zhang, Jin-San / Tsai, Wan-Chi / Siveke, Jens / Schildhaus, Hans-Ulrich / Ströbel, Philipp / Johnsen, Steven A / Ellenrieder, Volker / Hessmann, Elisabeth. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany. · Signaling and Transcription Laboratory, Department of Gastroenterology, Philipp's University, Marburg, Germany. · II. Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität, Munich, Germany. · Institute of Pathology, University Medical Center Göttingen, Germany. · Department of Internal Medicine I, University Medical Center Halle, Germany. · Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany. · 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. · Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan. · 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. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Germany. Electronic address: elisabeth.hessmann@med.uni-goettingen.de. ·Gastroenterology · Pubmed #28188746.

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.

15 Article GSK-3β Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression. 2016

Baumgart, Sandra / Chen, Nai-Ming / Zhang, Jin-San / Billadeau, Daniel D / Gaisina, Irina N / Kozikowski, Alan P / Singh, Shiv K / Fink, Daniel / Ströbel, Philipp / Klindt, Caroline / Zhang, Lizhi / Bamlet, William R / Koenig, Alexander / Hessmann, Elisabeth / Gress, Thomas M / Ellenrieder, Volker / Neesse, Albrecht. ·Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, University of Marburg, Marburg, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota. · Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois. · Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona. · Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany. · Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota. · Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, Minnesota. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. albrecht.neesse@med.uni-goettingen.de. ·Mol Cancer Ther · Pubmed #26823495.

ABSTRACT: We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3β (GSK-3β) 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-3β-dependent SP2 phosphorylation mediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3β also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3β-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-3β 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 GSK-3β 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-3β is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer.

16 Article Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. 2015

Mazur, Pawel K / Herner, Alexander / Mello, Stephano S / Wirth, Matthias / Hausmann, Simone / Sánchez-Rivera, Francisco J / Lofgren, Shane M / Kuschma, Timo / Hahn, Stephan A / Vangala, Deepak / Trajkovic-Arsic, Marija / Gupta, Aayush / Heid, Irina / Noël, Peter B / Braren, Rickmer / Erkan, Mert / Kleeff, Jörg / Sipos, Bence / Sayles, Leanne C / Heikenwalder, Mathias / Heßmann, Elisabeth / Ellenrieder, Volker / Esposito, Irene / Jacks, Tyler / Bradner, James E / Khatri, Purvesh / Sweet-Cordero, E Alejandro / Attardi, Laura D / Schmid, Roland M / Schneider, Guenter / Sage, Julien / Siveke, Jens T. ·Department of Pediatrics, Stanford University School of Medicine, California, USA. · Department of Genetics, Stanford University School of Medicine, California, USA. · Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Radiation Oncology, Stanford University School of Medicine, California, USA. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. · Department of Medicine, Stanford University School of Medicine, California, USA. · Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Ruhr-University Bochum, Medical Clinic, Knappschaftskrankenhaus, Bochum, Germany. · Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Pathology, University of Tübingen, Tübingen, Germany. · Institute of Virology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research center (DKFZ) Heidelberg, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. · Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Nat Med · Pubmed #26390243.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.

17 Article [Pancreatic cancer stroma: oncologist's ally or foe?]. 2015

Neesse, A / Ellenrieder, V. · ·Z Gastroenterol · Pubmed #25860583.

ABSTRACT: -- No abstract --

18 Article NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas. 2015

Chen, Nai-Ming / Singh, Garima / Koenig, Alexander / Liou, Geou-Yarh / Storz, Peter / Zhang, Jin-San / Regul, Lisanne / Nagarajan, Sankari / Kühnemuth, Benjamin / Johnsen, Steven A / Hebrok, Matthias / Siveke, Jens / Billadeau, Daniel D / Ellenrieder, Volker / Hessmann, Elisabeth. ·Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. · Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps-University, Marburg, Germany. · Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota. · Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida. · 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, People's Republic of China. · Clinic for General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany. · Diabetes Center, University of California San Francisco, San Francisco, California. · II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität, Munich, Germany. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota. · Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. Electronic address: elisabeth.hessmann@med.uni-goettingen.de. ·Gastroenterology · Pubmed #25623042.

ABSTRACT: BACKGROUND & AIMS: Oncogenic mutations in KRAS contribute to the development of pancreatic ductal adenocarcinoma, but are not sufficient to initiate carcinogenesis. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. Herein we sought to identify the mechanisms that link EGFR signaling with activation of SOX9 during acinar-ductal metaplasia, a transdifferentiation process that precedes pancreatic carcinogenesis. METHODS: We analyzed pancreatic tissues from Kras(G12D);pdx1-Cre and Kras(G12D);NFATc1(Δ/Δ);pdx1-Cre mice after intraperitoneal administration of caerulein, vs cyclosporin A or dimethyl sulfoxide (controls). Induction of EGFR signaling and its effects on the expression of Nuclear factor of activated T cells c1 (NFATc1) or SOX9 were investigated by quantitative reverse-transcription polymerase chain reaction, immunoblot, and immunohistochemical analyses of mouse and human tissues and acinar cell explants. Interactions between NFATc1 and partner proteins and effects on DNA binding or chromatin modifications were studied using co-immunoprecipitation and chromatin immunoprecipitation assays in acinar cell explants and mouse tissue. RESULTS: EGFR activation induced expression of NFATc1 in metaplastic areas from patients with chronic pancreatitis and in pancreatic tissue from Kras(G12D) mice. EGFR signaling also promoted formation of a complex between NFATc1 and C-JUN in dedifferentiating mouse acinar cells, leading to activation of Sox9 transcription and induction of acinar-ductal metaplasia. Pharmacologic inhibition of NFATc1 or disruption of the Nfatc1 gene inhibited EGFR-mediated induction of Sox9 transcription and blocked acinar-ductal transdifferentiation and pancreatic cancer initiation in mice. CONCLUSIONS: EGFR signaling induces expression of NFATc1 and Sox9, leading to acinar cell transdifferentiation and initiation of pancreatic cancer. Strategies designed to disrupt this pathway might be developed to prevent pancreatic cancer initiation in high-risk patients with chronic pancreatitis.

19 Article Antithetical NFATc1-Sox2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity. 2015

Singh, Shiv K / Chen, Nai-Ming / Hessmann, Elisabeth / Siveke, Jens / Lahmann, Marlen / Singh, Garima / Voelker, Nadine / Vogt, Sophia / Esposito, Irene / Schmidt, Ansgar / Brendel, Cornelia / Stiewe, Thorsten / Gaedcke, Jochen / Mernberger, Marco / Crawford, Howard C / Bamlet, William R / Zhang, Jin-San / Li, Xiao-Kun / Smyrk, Thomas C / Billadeau, Daniel D / Hebrok, Matthias / Neesse, Albrecht / Koenig, Alexander / Ellenrieder, Volker. ·Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg, Germany. · Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany. · II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität, Munich, Germany. · Institute for Molecular Tumor Biology, Philipps University, Marburg, Germany. · Institute of Pathology, Helmholtz Zentrum, Munich, Germany. · Institute of Pathology, Philipps University, Marburg, Germany. · Department of Hematology and Oncology, Philipps University, Marburg, Germany. · Department of Surgery, University Medical Center Goettingen, Goettingen, Germany. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL, USA. · Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, MN, USA. · Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China. · School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, China. · Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA. · Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA. · Diabetes Center, USCF, San Francisco, CA, USA. · Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany Division of Oncology Research, Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA. · Department of Gastroenterology II, University Medical Center Goettingen, Goettingen, Germany volker.ellenrieder@med.uni-goettingen.de. ·EMBO J · Pubmed #25586376.

ABSTRACT: In adaptation to oncogenic signals, pancreatic ductal adenocarcinoma (PDAC) cells undergo epithelial-mesenchymal transition (EMT), a process combining tumor cell dedifferentiation with acquisition of stemness features. However, the mechanisms linking oncogene-induced signaling pathways with EMT and stemness remain largely elusive. Here, we uncover the inflammation-induced transcription factor NFATc1 as a central regulator of pancreatic cancer cell plasticity. In particular, we show that NFATc1 drives EMT reprogramming and maintains pancreatic cancer cells in a stem cell-like state through Sox2-dependent transcription of EMT and stemness factors. Intriguingly, NFATc1-Sox2 complex-mediated PDAC dedifferentiation and progression is opposed by antithetical p53-miR200c signaling, and inactivation of the tumor suppressor pathway is essential for tumor dedifferentiation and dissemination both in genetically engineered mouse models (GEMM) and human PDAC. Based on these findings, we propose the existence of a hierarchical signaling network regulating PDAC cell plasticity and suggest that the molecular decision between epithelial cell preservation and conversion into a dedifferentiated cancer stem cell-like phenotype depends on opposing levels of p53 and NFATc1 signaling activities.

20 Article The transcription factor GLI1 interacts with SMAD proteins to modulate transforming growth factor β-induced gene expression in a p300/CREB-binding protein-associated factor (PCAF)-dependent manner. 2014

Nye, Monica D / Almada, Luciana L / Fernandez-Barrena, Maite G / Marks, David L / Elsawa, Sherine F / Vrabel, Anne / Tolosa, Ezequiel J / Ellenrieder, Volker / Fernandez-Zapico, Martin E. ·From the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905. · the Department of Biological Sciences, Northern Illinois University, De Kalb, Illinois 60115. · the Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps-University of Marburg, 35037 Marburg, Germany, and. · From the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905 fernandezzapico.martin@mayo.edu. ·J Biol Chem · Pubmed #24739390.

ABSTRACT: The biological role of the transcription factor GLI1 in the regulation of tumor growth is well established; however, the molecular events modulating this phenomenon remain elusive. Here, we demonstrate a novel mechanism underlying the role of GLI1 as an effector of TGFβ signaling in the regulation of gene expression in cancer cells. TGFβ stimulates GLI1 activity in cancer cells and requires its transcriptional activity to induce BCL2 expression. Analysis of the mechanism regulating this interplay identified a new transcriptional complex including GLI1 and the TGFβ-regulated transcription factor, SMAD4. We demonstrate that SMAD4 physically interacts with GLI1 for concerted regulation of gene expression and cellular survival. Activation of the TGFβ pathway induces GLI1-SMAD4 complex binding to the BCL2 promoter whereas disruption of the complex through SMAD4 RNAi depletion impairs GLI1-mediated transcription of BCL2 and cellular survival. Further characterization demonstrated that SMAD2 and the histone acetyltransferase, PCAF, participate in this regulatory mechanism. Both proteins bind to the BCL2 promoter and are required for TGFβ- and GLI1-stimulated gene expression. Moreover, SMAD2/4 RNAi experiments showed that these factors are required for the recruitment of GLI1 to the BCL2 promoter. Finally, we determined whether this novel GLI1 transcriptional pathway could regulate other TGFβ targets. We found that two additional TGFβ-stimulated genes, INTERLEUKIN-7 and CYCLIN D1, are dependent upon the intact GLI1-SMAD-PCAF complex for transcriptional activation. Collectively, these results define a novel epigenetic mechanism that uses the transcription factor GLI1 and its associated complex as a central effector to regulate gene expression in cancer cells.

21 Article Inflammation-induced NFATc1-STAT3 transcription complex promotes pancreatic cancer initiation by KrasG12D. 2014

Baumgart, Sandra / Chen, Nai-Ming / Siveke, Jens T / König, Alexander / Zhang, Jin-San / Singh, Shiv K / Wolf, Elmar / Bartkuhn, Marek / Esposito, Irene / Heßmann, Elisabeth / Reinecke, Johanna / Nikorowitsch, Julius / Brunner, Marius / Singh, Garima / Fernandez-Zapico, Martin E / Smyrk, Thomas / Bamlet, William R / Eilers, Martin / Neesse, Albrecht / Gress, Thomas M / Billadeau, Daniel D / Tuveson, David / Urrutia, Raul / Ellenrieder, Volker. ·Authors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Authors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkAuthors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Authors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkAuthors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New YorkAuthors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg · Authors' Affiliations:Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps University, Marburg; Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen; II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität; Institute of Pathology, Helmholtz Zentrum, Munich; Theodor Boveri Institute, University of Würzburg, Würzburg; Institute for Genetics, Justus-Liebig-University, Giessen, Germany; Schulze Center for Novel Therapeutics, Division of Oncology Research; Divisions of Anatomic Pathology and Biostatistics, College of Medicine; Laboratory of Epigenetics and Chromatin Dynamics, Department of Medicine, Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York urrutia.raul@mayo.edu ellenrie@med.uni-marburg.de. ·Cancer Discov · Pubmed #24694735.

ABSTRACT: SIGNIFICANCE: Our study points to the existence of an oncogenic NFATc1-STAT3 cooperativity that mechanistically links inflammation with pancreatic cancer initiation and progression. Because NFATc1-STAT3 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.

22 Article Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells. 2014

Zhang, J-S / Herreros-Villanueva, M / Koenig, A / Deng, Z / de Narvajas, A A-M / Gomez, T S / Meng, X / Bujanda, L / Ellenrieder, V / Li, X K / Kaufmann, S H / Billadeau, D D. ·1] Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA [2] School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, PR China. · 1] Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Gastroenterology and Endocrinology, Philipps University of Marburg, Marburg, Germany. · 1] Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA [2] Department of Pathophysiology, Qiqihar Medical University, Qiqihar, PR China. · Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA. · Department of Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco UPV/EHU, San Sebastián, Spain. · Department of Gastroenterology and Endocrinology, Philipps University of Marburg, Marburg, Germany. · School of Pharmaceutical Sciences and Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, PR China. ·Cell Death Dis · Pubmed #24675460.

ABSTRACT: While TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma (PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents. Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated depletion of either GSK-3α or GSK-3β. In contrast, depletion of GSK-3β, but not GSK-3α, sensitized PDA cell lines to TNFα-induced cell death. Further experiments demonstrated that TNFα-stimulated IκBα phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3β-deficient MEFs. Nonetheless, inhibition of GSK-3β function in MEFs or PDA cell lines impaired the expression of the NF-κB target genes Bcl-xL and cIAP2, but not IκBα. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3β targeted to the nucleus but not GSK-3β targeted to the cytoplasm, suggesting that GSK-3β regulates NF-κB function within the nucleus. Consistent with this notion, chromatin immunoprecipitation demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL. Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3 inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the sensitization by GSK-3 inhibition. These results not only suggest that GSK-3β overexpression and nuclear localization contribute to TNFα and TRAIL resistance via anti-apoptotic NF-κB genes such as Bcl-xL, but also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL for the treatment of PDA.

23 Article SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. 2014

Neesse, Albrecht / Frese, Kristopher K / Chan, Derek S / Bapiro, Tashinga E / Howat, William J / Richards, Frances M / Ellenrieder, Volker / Jodrell, Duncan I / Tuveson, David A. ·Cancer Research UK Cambridge Institute, The University of Cambridge, , Cambridge, UK. ·Gut · Pubmed #24067278.

ABSTRACT: DESIGN: Pharmacokinetic and pharmacodynamic parameters of cremophor-paclitaxel, nab-paclitaxel (human-albumin-bound paclitaxel, Abraxane) and a novel mouse-albumin-bound paclitaxel (m-nab-paclitaxel) were evaluated in genetically engineered mouse models (GEMMs) by liquid chromatography-tandem mass spectrometry (LC-MS/MS), histological and biochemical analysis. Preclinical evaluation of m-nab-paclitaxel included assessment by three-dimensional high-resolution ultrasound and molecular analysis in a novel secreted protein acidic and rich in cysteine (SPARC)-deficient GEMM of pancreatic ductal adenocarcinoma (PDA). RESULTS: nab-Paclitaxel exerted its antitumoural effects in a dose-dependent manner and was associated with less toxicity compared with cremophor-paclitaxel. SPARC nullizygosity in a GEMM of PDA, Kras(G12D);p53(flox/-);p48Cre (KPfC), resulted in desmoplastic ductal pancreas tumours with impaired collagen maturation. Paclitaxel concentrations were significantly decreased in SPARC null plasma samples and tissues when administered as low-dose m-nab-paclitaxel. At the maximally tolerated dose, SPARC deficiency did not affect the intratumoural paclitaxel concentration, stromal deposition and the immediate therapeutic response. CONCLUSIONS: nab-Paclitaxel accumulates and acts in a dose-dependent manner. The interaction of plasma SPARC and albumin-bound drugs is observed at low doses of nab-paclitaxel but is saturated at therapeutic doses in murine tumours. Thus, this study provides important information for future preclinical and clinical trials in PDA using nab-paclitaxel in combination with novel experimental and targeted agents.

24 Article WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic cancer. 2013

Griesmann, Heidi / Ripka, Stefanie / Pralle, Moritz / Ellenrieder, Volker / Baumgart, Sandra / Buchholz, Malte / Pilarsky, Christian / Aust, Daniela / Gress, Thomas M / Michl, Patrick. ·Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University, D-35043 Marburg, Germany. ·Neoplasia · Pubmed #23359789.

ABSTRACT: INTRODUCTION: WNT5A belongs to the Wnt family of secreted signaling molecules. Using transcriptional profiling, we previously identified WNT5A as target of the antiapoptotic transcription factor CUX1 and demonstrated high expression levels in pancreatic cancer. However, the impact of WNT5A on drug resistance and the signaling pathways employed by WNT5A remain to be elucidated. OBJECTIVES: This project aims to decipher the impact of WNT5A on resistance to apoptosis and the signaling pathways employed by WNT5A in pancreatic cancer. METHODS: The impact of WNT5A and its downstream effectors on tumor growth and drug resistance was studied in vitro and in xenograft models in vivo. Tissue microarrays of pancreatic cancer specimens were employed for immunohistochemical studies. RESULTS: Knockdown of WNT5A results in a significant increase in drug-induced apoptosis. In contrast, overexpression of WNT5A or addition of recombinant WNT5A mediates resistance to apoptosis in vitro. In our attempt to identify downstream effectors of WNT5A, we identified the transcription factor nuclear factor of activated T cells c2 (NFATc2) as transcriptional target of WNT5A signaling. NFATc2 confers a strong antiapoptotic phenotype mediating at least in part the effects of WNT5A on drug resistance and tumor cell survival. In vivo, WNT5A expression leads to resistance to gemcitabine-induced apoptosis in a xenograft model, which is paralleled by up-regulation of NFATc2. Both WNT5A and NFATc2 proteins are highly expressed in human pancreatic cancer tissues and their expression levels correlated significantly. CONCLUSION: We identified the WNT5A-NFATc2 axis as important mediator of drug resistance in pancreatic cancer.

25 Article Restricted heterochromatin formation links NFATc2 repressor activity with growth promotion in pancreatic cancer. 2012

Baumgart, Sandra / Glesel, Elisabeth / Singh, Garima / Chen, Nai-Ming / Reutlinger, Kristina / Zhang, Jinsan / Billadeau, Daniel D / Fernandez-Zapico, Martin E / Gress, Thomas M / Singh, Shiv K / Ellenrieder, Volker. ·Signaling and Transcription Laboratory, Department of Gastroenterology, Philipps-University of Marburg, Marburg, Germany. ·Gastroenterology · Pubmed #22079596.

ABSTRACT: BACKGROUND & AIMS: Transcriptional silencing of the p15(INK4b) tumor suppressor pathway overcomes cellular protection against unrestrained proliferation in cancer. Here we show a novel pathway involving the oncogenic transcription factor nuclear factor of activated T cells (NFAT) c2 targeting a p15(INK4b)-mediated failsafe mechanism to promote pancreatic cancer tumor growth. METHODS: Immunohistochemistry, real-time polymerase chain reaction, immunoblotting, and immunofluorescence microscopy were used for expression studies. Cancer growth was assessed in vitro by [(3)H]thymidine incorporation, colony formation assays, and in vivo using xenograft tumor models. Protein-protein interactions, promoter regulation, and local histone modifications were analyzed by immunoprecipitation, DNA pull-down, reporter, and chromatin immunoprecipitation assays. RESULTS: Our study uncovered induction of NFATc2 in late-stage pancreatic intraepithelial neoplasia lesions with increased expression in tumor cell nuclei of advanced cancers. In the nucleus, NFATc2 targets the p15(INK4b) promoter for inducible heterochromatin formation and silencing. NFATc2 binding to its cognate promoter site induces stepwise recruitment of the histone methyltransferase Suv39H1, causes local H3K9 trimethylation, and allows docking of heterochromatin protein HP1γ to the repressor complex. Conversely, inactivation of NFATc2 disrupts this repressor complex assembly and local heterochromatin formation, resulting in restoration of p15(INK4b) expression and inhibition of pancreatic cancer growth in vitro and in vivo. CONCLUSIONS: Here we describe a novel mechanism for NFATc2-mediated gene regulation and identify a functional link among its repressor activity, the silencing of the suppressor pathway p15(INK4b), and its pancreatic cancer growth regulatory functions. Thus, we provide evidence that inactivation of oncogenic NFATc2 might be an attractive strategy in treatment of pancreatic cancer.

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