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Pancreatic Neoplasms: HELP
Articles by Nathalia A. Giese
Based on 66 articles published since 2009
(Why 66 articles?)
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Between 2009 and 2019, N. A. Giese wrote the following 66 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Article None 2018

Heining, Christoph / Horak, Peter / Uhrig, Sebastian / Codo, Paula L / Klink, Barbara / Hutter, Barbara / Fröhlich, Martina / Bonekamp, David / Richter, Daniela / Steiger, Katja / Penzel, Roland / Endris, Volker / Ehrenberg, Karl Roland / Frank, Stephanie / Kleinheinz, Kortine / Toprak, Umut H / Schlesner, Matthias / Mandal, Ranadip / Schulz, Lothar / Lambertz, Helmut / Fetscher, Sebastian / Bitzer, Michael / Malek, Nisar P / Horger, Marius / Giese, Nathalia A / Strobel, Oliver / Hackert, Thilo / Springfeld, Christoph / Feuerbach, Lars / Bergmann, Frank / Schröck, Evelin / von Kalle, Christof / Weichert, Wilko / Scholl, Claudia / Ball, Claudia R / Stenzinger, Albrecht / Brors, Benedikt / Fröhling, Stefan / Glimm, Hanno. ·Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. · University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · German Cancer Research Center (DKFZ), Heidelberg, Germany. · German Cancer Consortium (DKTK), Dresden, Germany. · Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany. · Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany. · DKTK, Heidelberg, Germany. · Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany. · Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. · Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany. · Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. · National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. · Division of Radiology, DKFZ, Heidelberg, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · DKTK, Munich, Germany. · Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. · Department of Medical Oncology, NCT, Heidelberg, Germany. · Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany. · Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and BioQuant, Heidelberg University, Heidelberg, Germany. · Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany. · Division of Applied Functional Genomics, DKFZ, Heidelberg, Germany. · Department of Oncology, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany. · Department of Oncology, Sana Kliniken Lübeck, Lübeck, Germany. · Department of Gastroenterology, Hepatology and Infectious Diseases, Tübingen University Hospital, Tübingen, Germany. · DKTK, Tübingen, Germany. · Department of Radiology, Tübingen University Hospital, Tübingen, Germany. · Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany. · DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany. · Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany. hanno.glimm@nct-dresden.de stefan.froehling@nct-heidelberg.de. · Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. hanno.glimm@nct-dresden.de stefan.froehling@nct-heidelberg.de. ·Cancer Discov · Pubmed #29802158.

ABSTRACT: We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with

2 Article Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer. 2018

Bauer, Andrea S / Nazarov, Petr V / Giese, Nathalia A / Beghelli, Stefania / Heller, Anette / Greenhalf, William / Costello, Eithne / Muller, Arnaud / Bier, Melanie / Strobel, Oliver / Hackert, Thilo / Vallar, Laurent / Scarpa, Aldo / Büchler, Markus W / Neoptolemos, John P / Kreis, Stephanie / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany. · Genomics and Proteomics Research Unit, Luxembourg Institute of Health, Luxembourg City, Luxembourg. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine Centre, Liverpool, United Kingdom. · Life Sciences Research Unit, University of Luxembourg, Luxembourg City, Luxembourg. ·Int J Cancer · Pubmed #28983920.

ABSTRACT: Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non-tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy-related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy-related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.

3 Article SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival. 2017

Mohelnikova-Duchonova, Beatrice / Strouhal, Ondrej / Hughes, David J / Holcatova, Ivana / Oliverius, Martin / Kala, Zdenek / Campa, Daniele / Rizzato, Cosmeri / Canzian, Federico / Pezzilli, Raffaele / Talar-Wojnarowska, Renata / Malecka-Panas, Ewa / Sperti, Cosimo / Federico Zambon, Carlo / Pedrazzoli, Sergio / Fogar, Paola / Milanetto, Anna Caterina / Capurso, Gabriele / Delle Fave, Gianfranco / Valente, Roberto / Gazouli, Maria / Malleo, Giuseppe / Teresa Lawlor, Rita / Strobel, Oliver / Hackert, Thilo / Giese, Nathalia / Vodicka, Pavel / Vodickova, Ludmila / Landi, Stefano / Tavano, Francesca / Gioffreda, Domenica / Piepoli, Ada / Pazienza, Valerio / Mambrini, Andrea / Pedata, Mariangela / Cantore, Maurizio / Bambi, Franco / Ermini, Stefano / Funel, Niccola / Lemstrova, Radmila / Soucek, Pavel. ·Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic. · Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. · Department of Physiology &Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland. · Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Transplantation Surgery, Institute of Clinical and Experimental Medicine, Prague, Czech Republic. · Department of Surgery, The University Hospital and Faculty of Medicine, Brno Bohunice, Czech Republic. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Biology, University of Pisa, Pisa, Italy. · Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · Department of Digestive Diseases, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Italy. · Department of Medicine - DIMED, University of Padova, Italy. · Clinica Chirurgica 4, University of Padova, Italy. · Department of Laboratory Medicine, University-Hospital of Padova, Italy. · Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Department of Surgery and Oncology, University and Hospital Trust of Verona, Verona, Italy. · ARC-NET Applied research on Cancer Centre, University and Hospital Trust of Verona, Verona, Italy. · Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic and First Faculty of Medicine, Charles University in Prague, Czech Republic. · Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy. · Blood Transfusion Service, Children's Hospital Meyer, Azienda Ospedaliero Universitaria, Florence, Italy. ·Sci Rep · Pubmed #28272475.

ABSTRACT: Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

4 Article Comparison of the tumor cell secretome and patient sera for an accurate serum-based diagnosis of pancreatic ductal adenocarcinoma. 2017

Mustafa, Shakhawan / Pan, Longqiang / Marzoq, Aseel / Fawaz, Malak / Sander, Laureen / Rückert, Felix / Schrenk, Andrea / Hartl, Christina / Uhler, Rico / Yildirim, Adem / Strobel, Oliver / Hackert, Thilo / Giese, Nathalia / Büchler, Markus W / Hoheisel, Jörg D / Alhamdani, Mohamed Saiel Saeed. ·Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. · Kurdistan Institution for Strategic Studies and Scientific Research, Kurdistan Region, Iraq. · Chirurgische Klinik, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. ·Oncotarget · Pubmed #28060763.

ABSTRACT: Pancreatic cancer is the currently most lethal malignancy. Toward an accurate diagnosis of the disease in body liquids, we studied the protein composition of the secretomes of 16 primary and established cell lines of pancreatic ductal adenocarcinoma (PDAC). Compared to the secretome of non-tumorous cells, 112 proteins exhibited significantly different abundances. Functionally, the proteins were associated with PDAC features, such as decreased apoptosis, better cell survival and immune cell regulation. The result was compared to profiles obtained from 164 serum samples from two independent cohorts - a training and a test set - of patients with PDAC or chronic pancreatitis and healthy donors. Eight of the 112 secretome proteins exhibited similar variations in their abundance in the serum profile specific for PDAC patients, which was composed of altogether 189 proteins. The 8 markers shared by secretome and serum yielded a 95.1% accuracy of distinguishing PDAC from healthy in a Receiver Operating Characteristic curve analysis, while any number of serum-only markers produced substantially less accurate results. Utility of the identified markers was confirmed by classical enzyme linked immunosorbent assays (ELISAs). The study highlights the value of cell secretome analysis as a means of defining reliable serum biomarkers.

5 Article Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice. 2016

Jandaghi, Pouria / Najafabadi, Hamed S / Bauer, Andrea S / Papadakis, Andreas I / Fassan, Matteo / Hall, Anita / Monast, Anie / von Knebel Doeberitz, Magnus / Neoptolemos, John P / Costello, Eithne / Greenhalf, William / Scarpa, Aldo / Sipos, Bence / Auld, Daniel / Lathrop, Mark / Park, Morag / Büchler, Markus W / Strobel, Oliver / Hackert, Thilo / Giese, Nathalia A / Zogopoulos, George / Sangwan, Veena / Huang, Sidong / Riazalhosseini, Yasser / Hoheisel, Jörg D. ·Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. · Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany. · Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK. · ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · Institute for Pathology and Neuropathology, Universitätsklinikum Tübingen, Tübingen, Germany. · Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montréal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. Electronic address: Yasser.riazalhosseini@mcgill.ca. ·Gastroenterology · Pubmed #27578530.

ABSTRACT: BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer.

6 Article Establishment and Characterization of a Novel Cell Line, ASAN-PaCa, Derived From Human Adenocarcinoma Arising in Intraductal Papillary Mucinous Neoplasm of the Pancreas. 2016

Heller, Anette / Angelova, Assia L / Bauer, Sonja / Grekova, Svitlana P / Aprahamian, Marc / Rommelaere, Jean / Volkmar, Michael / Janssen, Johannes W G / Bauer, Nathalie / Herr, Ingrid / Giese, Thomas / Gaida, Matthias M / Bergmann, Frank / Hackert, Thilo / Fritz, Stefan / Giese, Nathalia A. ·From the *Department of Surgery, University Hospital Heidelberg; †Infection and Cancer Program, Tumor Virology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany; ‡Institut de Recherche Contre les Cancers de l'Appareil Digestif (IRCAD), Strasbourg, France; §Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ); ∥Institute of Human Genetics, Cytogenetic, University Hospital Heidelberg; ¶Molecular OncoSurgery Group, Department of General and Transplantation Surgery, University of Heidelberg and German Cancer Research Center; and Institutes of #Immunology, and **Pathology, University Hospital Heidelberg, Heidelberg, Germany. ·Pancreas · Pubmed #27518460.

ABSTRACT: OBJECTIVES: Our aim was to establish and characterize a novel pancreatic ductal adenocarcinoma cell line from a patient in whom the origin of the invasive carcinoma could be traced back to the intraductal papillary mucinous neoplasm (IPMN) precursor lesion. METHODS: The primary patient-derived tumor was propagated in immunocompromised mice for 2 generations and used to establish a continuous in vitro culture termed ASAN-PaCa. Transplantation to fertilized chicken eggs confirmed the tumorigenic potential in vivo. Molecular analyses included karyotyping, next-generation genomic sequencing, expression analysis of marker proteins, and mucin-profiling. RESULTS: The analysis of marker proteins confirmed the epithelial nature of the established cell line, and revealed that the expression of the mucin MUC1 was higher than that of MUC2 and MUC5AC. ASAN-PaCa cells showed rapid in vitro and in vivo growth and multiple chromosomal aberrations. They harbored mutations in KRAS (Q61H), TP53 (Y220C), and RNF43 (I47V and L418M) but lacked either IPMN-specific GNAS or presumed pancreatic ductal adenocarcinoma-driving mutations in KRAS (codons 12/13), SMAD, and CDKN2A genes. CONCLUSIONS: ASAN-PaCa cell line represents a novel preclinical model of pancreatic adenocarcinoma arising in the background of IPMN, and offers an opportunity to study how further introduction of known driver mutations might contribute to pancreatic carcinogenesis.

7 Article Association of genetic polymorphisms with survival of pancreatic ductal adenocarcinoma patients. 2016

Rizzato, Cosmeri / Campa, Daniele / Talar-Wojnarowska, Renata / Halloran, Christopher / Kupcinskas, Juozas / Butturini, Giovanni / Mohelníková-Duchoňová, Beatrice / Sperti, Cosimo / Tjaden, Christine / Ghaneh, Paula / Hackert, Thilo / Funel, Niccola / Giese, Nathalia / Tavano, Francesca / Pezzilli, Raffaele / Pedata, Mariangela / Pasquali, Claudio / Gazouli, Maria / Mambrini, Andrea / Souček, Pavel / di Sebastiano, Pierluigi / Capurso, Gabriele / Cantore, Maurizio / Oliverius, Martin / Offringa, Rienk / Małecka-Panas, Ewa / Strobel, Oliver / Scarpa, Aldo / Canzian, Federico. ·Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, Department of Translational Research and New Technologies in Medicine and Surgery and. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, Department of Biology, University of Pisa, Pisa, Italy. · Department of Digestive Tract Diseases, Medical University of Łódź, Łódź, Poland. · Department of Molecular and Clinical Cancer Medicine, NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, UK. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Unit of Surgery B, The Pancreas Institute, Department of Surgery and Oncology, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy. · Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. · Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy. · Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Translational Research and New Technologies in Medicine and Surgery and. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo (FG), Italy. · Pancreas Unit, Department of Digestive Disease, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Oncological Department, ASL 1 Massa Carrara, Massa Carrara, Italy. · Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · Transplant Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. · Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany and. · ARC-NET, Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, f.canzian@dkfz.de. ·Carcinogenesis · Pubmed #27497070.

ABSTRACT: Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials.

8 Article The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer. 2016

Johansen, Julia S / Calatayud, Dan / Albieri, Vanna / Schultz, Nicolai A / Dehlendorff, Christian / Werner, Jens / Jensen, Benny V / Pfeiffer, Per / Bojesen, Stig E / Giese, Nathalia / Nielsen, Kaspar R / Nielsen, Svend E / Yilmaz, Mette / Holländer, Niels H / Andersen, Klaus K. ·Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark. julia.johansen@post3.tele.dk. · Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark. julia.johansen@post3.tele.dk. · Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark. · Danish Cancer Society Research Center, Danish Cancer Society, Denmark. · Department of General, Visceral, and Transplant Surgery, University of Heidelberg, Germany. · Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark. · Odense University Hospital, Germany. · Department of Oncology, Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark. · Department of Clinical Immunology, Aalborg University Hospital, Denmark. · Department of Oncology, Hillerød Hospital, Denmark. · Department of Oncology, Aalborg University Hospital, Denmark. · Department of Oncology, Naestved Hospital, Denmark. ·Int J Cancer · Pubmed #27464352.

ABSTRACT: Biomarkers for early diagnosis of patients with pancreatic cancer (PC) are needed. Our aim was to identify panels of miRNAs in serum in combination with CA 19-9 for use in the diagnosis of PC. Four hundred seventeen patients with PC were included prospectively from Denmark (n = 306) and Germany (n = 111). Controls included 59 patients with chronic pancreatitis (CP) and 248 healthy subjects (HS). MiRNAs were analyzed in pretreatment serum samples from 3 cohorts: discovery cohort (754 human miRNAs, TaqMan(®) Human MicroRNA assay, Applied Biosystem; PC n = 133, controls n = 72); training cohort (34 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 198, controls n = 184); validation cohort (13 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 86, controls n = 51). We found that 34 miRNAs in serum from PC patients in the discovery cohort were expressed differently than in controls. These miRNAs were tested in the training cohort, and four diagnostic panels were constructed that included 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, -191, -323.3p, -345 and -483.5p). Diagnostic accuracy of detecting PC in the training cohort was AUC (Index I 0.85; II 0.87; III 0.85; IV 0.95; CA 19-9 0.93); specificity (I 0.71; II 0.76; III 0.66; IV 0.90 (fixed sensitivity at 0.85); CA 19-9 0.93). Combining serum CA 19-9 and Index II best discriminated Stages I and II PC from HS [AUC 0.93 (0.90-0.96), sensitivity 0.77 (0.69-0.84), specificity 0.94 (0.90-0.96) and accuracy 0.88 (0.84-0.91)]. In conclusion, we identified four diagnostic panels based on 5 or 12 miRNAs in serum that could distinguish patients with PC from HS and CP.

9 Article Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression. 2016

Botla, Sandeep K / Savant, Soniya / Jandaghi, Pouria / Bauer, Andrea S / Mücke, Oliver / Moskalev, Evgeny A / Neoptolemos, John P / Costello, Eithne / Greenhalf, William / Scarpa, Aldo / Gaida, Matthias M / Büchler, Markus W / Strobel, Oliver / Hackert, Thilo / Giese, Nathalia A / Augustin, Hellmut G / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany. · Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. · National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK. · Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · Department of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faulty Mannheim, Heidelberg University, Mannheim, Germany. German Cancer Consortium, Heidelberg, Germany. · Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany. j.hoheisel@dkfz.de. ·Cancer Res · Pubmed #27216198.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.

10 Article CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. 2016

Noll, Elisa M / Eisen, Christian / Stenzinger, Albrecht / Espinet, Elisa / Muckenhuber, Alexander / Klein, Corinna / Vogel, Vanessa / Klaus, Bernd / Nadler, Wiebke / Rösli, Christoph / Lutz, Christian / Kulke, Michael / Engelhardt, Jan / Zickgraf, Franziska M / Espinosa, Octavio / Schlesner, Matthias / Jiang, Xiaoqi / Kopp-Schneider, Annette / Neuhaus, Peter / Bahra, Marcus / Sinn, Bruno V / Eils, Roland / Giese, Nathalia A / Hackert, Thilo / Strobel, Oliver / Werner, Jens / Büchler, Markus W / Weichert, Wilko / Trumpp, Andreas / Sprick, Martin R. ·Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany. · Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Pathology, University of Heidelberg, Heidelberg, Germany. · National Center for Tumor Diseases (NCT), Heidelberg, Germany. · Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany. · Heidelberg Pharma GmbH, Ladenburg, Germany. · Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany. · Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, Heidelberg, Germany. · Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center, Heidelberg, Germany. · Department of General and Visceral Surgery, University Hospital Heidelberg, Heidelberg, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. ·Nat Med · Pubmed #26855150.

ABSTRACT: Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel. Cytochrome P450 3A5 (CYP3A5) metabolizes these compounds in tumors of the exocrine-like subtype, and pharmacological or short hairpin RNA (shRNA)-mediated CYP3A5 inhibition sensitizes tumor cells to these drugs. Whereas hepatocyte nuclear factor 4, alpha (HNF4A) controls basal expression of CYP3A5, drug-induced CYP3A5 upregulation is mediated by the nuclear receptor NR1I2. CYP3A5 also contributes to acquired drug resistance in QM-PDA and classical PDAC, and it is highly expressed in several additional malignancies. These findings designate CYP3A5 as a predictor of therapy response and as a tumor cell-autonomous detoxification mechanism that must be overcome to prevent drug resistance.

11 Article Isolation and culture of primary human pancreatic stellate cells that reflect the context of their tissue of origin. 2016

Strobel, Oliver / Dadabaeva, Nigora / Felix, Klaus / Hackert, Thilo / Giese, Nathalia A / Jesenofsky, Ralf / Werner, Jens. ·Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. oliver.strobel@med.uni-heidelberg.de. · Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. · Department of Internal Medicine 2, University Medicine Mannheim, Mannheim, Germany. ·Langenbecks Arch Surg · Pubmed #26712717.

ABSTRACT: BACKGROUND: Pancreatic stellate cells (PSCs) play a critical role in pancreatic ductal adenocarcinoma (PDAC). Activated PSCs are the main source of fibrosis in chronic pancreatitis and of desmoplasia in PDAC. The majority of studies on PSC are based on in vitro experiments relying on immortalized cell lines derived from diseased human pancreas or from animal models. These PSCs are usually activated and may not represent the biological context of their tissue of origin. PURPOSE: (1) To isolate and culture primary human PSC from different disease contexts with minimal impact on their state of activation. (2) To perform a comparative analysis of phenotypes of PSC derived from different contexts. METHODS: PSCs were isolated from normal pancreas, chronic pancreatitis, and PDAC using a hybrid method of digestion and outgrowth. To minimize activation by serum compounds, cells were cultured in a low-serum environment (2.5 % fetal bovine serum (FBS)). Expression patterns of commonly used markers for PSC phenotype and activity were compared between primary PSC lines derived from different contexts and correlated to expression in their original tissues. RESULTS: Isolation was successful from 14 of 17 tissues (82 %). Isolated PSC displayed stable viability and phenotype in low-serum environment. Expression profiles of isolated PSC and matched original tissues were closely correlated. PDAC-derived PSC tended to have a higher status of activation if compared to PSC derived from non-cancerous tissues. CONCLUSIONS: Primary human PSCs isolated from different contexts and cultured in a low-serum environment maintain a phenotype that reflects the stromal activity present in their tissue of origin.

12 Article PLAC8 Localizes to the Inner Plasma Membrane of Pancreatic Cancer Cells and Regulates Cell Growth and Disease Progression through Critical Cell-Cycle Regulatory Pathways. 2016

Kaistha, Brajesh P / Lorenz, Holger / Schmidt, Harald / Sipos, Bence / Pawlak, Michael / Gierke, Berthold / Kreider, Ramona / Lankat-Buttgereit, Brigitte / Sauer, Melanie / Fiedler, Lisa / Krattenmacher, Anja / Geisel, Bettina / Kraus, Johann M / Frese, Kristopher K / Kelkenberg, Sabine / Giese, Nathalia A / Kestler, Hans A / Gress, Thomas M / Buchholz, Malte. ·Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany. · Central Imaging Facility, Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), Heidelberg, Germany. · Department of Pathology, University Clinic Tübingen, Tübingen, Germany. · Department of Biochemistry and Protein Profiling, NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany. · Medical Systems Biology, University of Ulm, Ulm, Germany. · Princess Margaret Hospital, University of Toronto, Toronto, Canada. · CeGaT GmbH, Tübingen, Germany. · Department of Surgery, University Clinic Heidelberg, Heidelberg, Germany. · Clinic for Gastroenterology, Endocrinology, Metabolism and Infectiology, Philipps-University Marburg, Marburg, Germany. malte.buchholz@staff.uni-marburg.de. ·Cancer Res · Pubmed #26669866.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) carries the most dismal prognosis of all solid tumors and is generally strongly resistant to currently available chemo- and/or radiotherapy regimens, including targeted molecular therapies. Therefore, unraveling the molecular mechanisms underlying the aggressive behavior of pancreatic cancer is a necessary prerequisite for the development of novel therapeutic approaches. We previously identified the protein placenta-specific 8 (PLAC8, onzin) in a genome-wide search for target genes associated with pancreatic tumor progression and demonstrated that PLAC8 is strongly ectopically expressed in advanced preneoplastic lesions and invasive human PDAC. However, the molecular function of PLAC8 remained unclear, and accumulating evidence suggested its role is highly dependent on cellular and physiologic context. Here, we demonstrate that in contrast to other cellular systems, PLAC8 protein localizes to the inner face of the plasma membrane in pancreatic cancer cells, where it interacts with specific membranous structures in a temporally and spatially stable manner. Inhibition of PLAC8 expression strongly inhibited pancreatic cancer cell growth by attenuating cell-cycle progression, which was associated with transcriptional and/or posttranslational modification of the central cell-cycle regulators CDKN1A, retinoblastoma protein, and cyclin D1 (CCND1), but did not impact autophagy. Moreover, Plac8 deficiency significantly inhibited tumor formation in genetically engineered mouse models of pancreatic cancer. Together, our findings establish PLAC8 as a central mediator of tumor progression in PDAC and as a promising candidate gene for diagnostic and therapeutic targeting.

13 Article Clinical Impact of Structured Follow-up After Pancreatic Surgery. 2016

Tjaden, Christine / Michalski, Christoph W / Strobel, Oliver / Giese, Nathalia / Hennche, Anne-Kathrin / Büchler, Markus W / Hackert, Thilo. ·From the *Department of Surgery, University of Heidelberg, Heidelberg; †Department of Orthopedics, Neckar-Odenwald-Kliniken, Mosbach, Germany. ·Pancreas · Pubmed #26646267.

ABSTRACT: OBJECTIVES: Structured follow-up after surgery for pancreatic ductal adenocarcinoma (PDAC) remains controversial and is currently not recommended due to a supposed lack of therapeutic consequences. Furthermore, it is not clear whether noncancer patients after pancreas resection need to be seen in the clinic on a regular basis. The present study analyzed how follow-up after pancreatic surgery affected postoperative treatment and long-term outcomes. METHODS: Data of all postoperative visits in a specialized outpatient clinic for pancreatic diseases were analyzed for a 1-year period with regard to symptoms, diagnostic procedures, and therapeutic consequences. RESULTS: Six hundred eighteen patients underwent 940 postoperative follow-ups. Nearly half of them needed a change of medication due to altered pancreatic function. In 74 (40%) of 184 resected PDAC patients, recurrence (local or systemic) was detected during follow-up, although only 19 of these had shown associated symptoms (26%). In all patients with recurrence, a cancer-directed treatment was induced. Eleven (69%) of 16 patients with isolated local recurrence were referred for reresection. CONCLUSIONS: Follow-up examinations are a substantial part of the clinical management after pancreas resections. Follow-up is particularly important for PDAC because recurrence is often asymptomatic, but its detection allows for therapeutic interventions and potentially improved prognosis. This should be implemented in future guidelines.

14 Article Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression. 2015

Alam, Muhammad S / Gaida, Matthias M / Bergmann, Frank / Lasitschka, Felix / Giese, Thomas / Giese, Nathalia A / Hackert, Thilo / Hinz, Ulf / Hussain, S Perwez / Kozlov, Serguei V / Ashwell, Jonathan D. ·Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Immunology, University of Heidelberg, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Pancreatic Cancer Unit, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. ·Nat Med · Pubmed #26479921.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323(+) T cells was associated with large numbers of tumor necrosis factor (TNF)-α- and interleukin (IL)-17-producing CD4(+) tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4(+) T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell-deficient mice. Notably, a plasma membrane-permeable peptide derived from GADD45-α, the naturally occurring inhibitor of p38 pY323(+) (ref. 7), reduced CD4(+) TIL production of TNF-α, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4(+) TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit.

15 Article Stratification of pancreatic tissue samples for molecular studies: RNA-based cellular annotation procedure. 2015

Heller, Anette / Gaida, Matthias M / Männle, D / Giese, Thomas / Scarpa, Aldo / Neoptolemos, John P / Hackert, Thilo / Strobel, Oliver / Hoheisel, Jörg D / Giese, Nathalia A / Bauer, Andrea S. ·Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: anette.heller@med.uni-heidelberg.de. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Pathology and ARC-NET Research Centre, University of Verona, Verona, Italy. · National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine Centre, Liverpool, UK. · Functional Genome Analysis, German Research Cancer Center, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: nathalia.giese@med.uni-heidelberg.de. ·Pancreatology · Pubmed #26118650.

ABSTRACT: BACKGROUND/OBJECTIVES: Meaningful profiling of pancreatic cancer samples is particularly challenging due to their complex cellular composition. Beyond tumor cells, surgical biopsies contain desmoplastic stroma with infiltrating inflammatory cells, adjacent normal parenchyma, and "non-pancreatic tissues". The risk of misinterpretation rises when the heterogeneous cancer tissues are sub-divided into smaller fragments for multiple analytic procedures. Pre-analytic histological evaluation is the best option to characterize pancreatic tissue samples. Our aim was to develop a complement or alternative procedure to determine the cellular composition of pancreatic cancerous biopsies, basing on intra-analytic molecular annotation. A standard process for sample stratification at a molecular level does not yet exist. Particularly in the case of retrospective or data depository-based studies, when hematoxylin-eosin stained sections are not available, it supports the correct interpretation of expression profiles. METHODS: A five-gene transcriptional signature (RNACellStrat) was defined that allows cell type-specific stratification of pancreatic tissues. Testing biopsy material from biobanks with this procedure demonstrated high correspondence of molecular (qRT-PCR and microarray) and histologic (hematoxylin-eosin stain) evaluations. RESULTS: Notably, about a quarter of randomly selected samples (tissue fragments) were exposed as inappropriate for subsequent clinico-pathological interpretation. CONCLUSIONS: Via immediate intra-analytical procedure, our RNA-based stratification RNACellStrat increases the accuracy and reliability of the conclusions drawn from diagnostic and prognostic molecular information.

16 Article TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. 2015

Campa, Daniele / Rizzato, Cosmeri / Stolzenberg-Solomon, Rachael / Pacetti, Paola / Vodicka, Pavel / Cleary, Sean P / Capurso, Gabriele / Bueno-de-Mesquita, H B As / Werner, Jens / Gazouli, Maria / Butterbach, Katja / Ivanauskas, Audrius / Giese, Nathalia / Petersen, Gloria M / Fogar, Paola / Wang, Zhaoming / Bassi, Claudio / Ryska, Miroslav / Theodoropoulos, George E / Kooperberg, Charles / Li, Donghui / Greenhalf, William / Pasquali, Claudio / Hackert, Thilo / Fuchs, Charles S / Mohelnikova-Duchonova, Beatrice / Sperti, Cosimo / Funel, Niccola / Dieffenbach, Aida Karina / Wareham, Nicholas J / Buring, Julie / Holcátová, Ivana / Costello, Eithne / Zambon, Carlo-Federico / Kupcinskas, Juozas / Risch, Harvey A / Kraft, Peter / Bracci, Paige M / Pezzilli, Raffaele / Olson, Sara H / Sesso, Howard D / Hartge, Patricia / Strobel, Oliver / Małecka-Panas, Ewa / Visvanathan, Kala / Arslan, Alan A / Pedrazzoli, Sergio / Souček, Pavel / Gioffreda, Domenica / Key, Timothy J / Talar-Wojnarowska, Renata / Scarpa, Aldo / Mambrini, Andrea / Jacobs, Eric J / Jamroziak, Krzysztof / Klein, Alison / Tavano, Francesca / Bambi, Franco / Landi, Stefano / Austin, Melissa A / Vodickova, Ludmila / Brenner, Hermann / Chanock, Stephen J / Delle Fave, Gianfranco / Piepoli, Ada / Cantore, Maurizio / Zheng, Wei / Wolpin, Brian M / Amundadottir, Laufey T / Canzian, Federico. ·Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic. · Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. · Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Department of Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN. · Department of Laboratory Medicine, University Hospital of Padua, Padua, Italy. · Surgical and Oncological Department, Pancreas Institute - University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Second Faculty of Medicine, Charles University in Prague and Central Military Hospital, Prague, Czech Republic. · 1st Department of Propaedeutic Surgery, School of Medicine, University of Athens, Athens, Greece. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. · Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX. · National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom. · Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. · Department of Oncology, Palacky University Medical School and Teaching Hospital in Olomouc, Olomouc, Czech Republic. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · German Cancer Consortium (DKTK), Heidelberg, Germany. · MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom. · Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. · Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Medicine - DIMED, University of Padua, Padua, Italy. · Department of Epidemiology and Public Health, Yale School of Public Health, New Haven, CT. · Department of Epidemiology, Harvard School of Public Health, Boston, MA. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. · Division of Epidemiology, Departments of Obstetrics and Gynecology, Environmental Medicine, and Population Health, New York University School of Medicine, New York, NY. · Surgical Clinic 4, University of Padua, Padua, Italy. · Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo Della Sofferenza,", San Giovanni Rotondo, Italy. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Epidemiology Research Program, American Cancer Society, Atlanta, GA. · Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD. · Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy. · Department of Biology, University of Pisa, Pisa, Italy. · Department of Epidemiology, University of Washington, Seattle, WA. · Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN. ·Int J Cancer · Pubmed #25940397.

ABSTRACT: A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

17 Article Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer. 2015

Zhang, Yiyao / Liu, Li / Fan, Pei / Bauer, Nathalie / Gladkich, Jury / Ryschich, Eduard / Bazhin, Alexandr V / Giese, Nathalia A / Strobel, Oliver / Hackert, Thilo / Hinz, Ulf / Gross, Wolfgang / Fortunato, Franco / Herr, Ingrid. ·Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Section Surgical Research, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China. ·Oncotarget · Pubmed #25846752.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA.

18 Article GHSR DNA hypermethylation is a common epigenetic alteration of high diagnostic value in a broad spectrum of cancers. 2015

Moskalev, Evgeny A / Jandaghi, Pouria / Fallah, Mahdi / Manoochehri, Mehdi / Botla, Sandeep K / Kolychev, Oleg V / Nikitin, Evgeny A / Bubnov, Vladymyr V / von Knebel Doeberitz, M / Strobel, Oliver / Hackert, Thilo / Büchler, Markus W / Giese, Nathalia / Bauer, Andrea / Muley, Thomas / Warth, Arne / Schirmacher, Peter / Haller, Florian / Hoheisel, Jörg D / Riazalhosseini, Yasser. ·Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. · Diagnostic Molecular Pathology, Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. · Molecular Genetic Epidemiology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. · Military Training Research Center, Zhukovsky - Gagarin Air Force Academy, Voronezh, Russia. · Molecular Haematology, National Research Centre for Haematology, Moscow, Russia. · Department of Genomics and Immunology, Odessa State Medical University, Odessa, Ukraine. · Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Translational Research Unit, Thoraxklinik Heidelberg at Heidelberg University, Heidelberg, Germany. · Department of Translational Pneumology, Translational Lung Research Centre Heidelberg (TLRC-H), Member of the German Centre for Lung Research (DZL), Heidelberg, Germany. · Institute of Pathology, University Hospital, Heidelberg, Germany. · Current address: Department of Human Genetics and McGill University and Genome Quebec Innovation Centre, Montreal, Quebec. ·Oncotarget · Pubmed #25557172.

ABSTRACT: Identification of a single molecular trait that is determinant of common malignancies may serve as a powerful diagnostic supplement to cancer type-specific markers. Here, we report a DNA methylation mark that is characteristic of seven studied malignancies, namely cancers of lung, breast, prostate, pancreas, colorectum, glioblastoma and B cell chronic lymphocytic leukaemia (CLL) (n = 137). This mark was defined by substantial hypermethylation at the promoter and first exon of growth hormone secretagouge receptor (GHSR) through bisulfite pyrosequencing. The degree of aberrant methylation was capable of accurate discrimination between cancer and control samples. The highest sensitivity and specificity of cancer detection was achieved for cancers of pancreas, lung, breast and CLL yielding the area under the curve (AUC) values of 1.0000, 0.9952, 0.9800 and 0.9400, respectively. Narrowing to a single CpG site within the gene's promoter or four consecutive CpG units of the highest methylation levels within the first exon improved the detection power. GHSR hypermethylation was detected already at the early stage tumors. The accurate performance of this marker was further replicated in an independent set of pancreatic cancer and control samples (n = 78). These findings support the candidature of GHSR methylation as a highly accurate pan-cancer marker.

19 Article Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity. 2015

Schenk, Miriam / Aykut, Berk / Teske, Christian / Giese, Nathalia A / Weitz, Juergen / Welsch, Thilo. ·Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany. · Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Germany. Electronic address: thilo.welsch@uniklinikum-dresden.de. ·Cancer Lett · Pubmed #25529011.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive growth, early metastasis and high resistance to chemotherapy. Salinomycin is a promising compound eliminating cancer stem cells and retarding cancer cell migration. The present study investigated the effectiveness of salinomycin against PDAC in vivo and elucidated the mechanism of PDAC growth inhibition. Salinomycin treatment was well tolerated by the mice and significantly reduced tumor growth after 19 days compared to the control group (each n = 16). There was a trend that salinomycin also impeded metastatic spread to the liver and peritoneum. Whereas salinomycin moderately induced apoptosis and retarded proliferation at 5-10 µM, it strongly inhibited cancer cell migration that was accompanied by a marked loss of actin stress fibers after 6-9 h. Salinomycin silenced RhoA activity, and loss of stress fibers could be reversed by Rho activation. Moreover, salinomycin dislocated fascin from filopodia and stimulated Rac-associated circular dorsal ruffle formation. In conclusion, salinomycin is an effective and promising compound against PDAC. Besides its known stem cell-specific cytotoxic effects, salinomycin blocks cancer cell migration by disrupting stress fiber integrity and affecting the mutual Rho-GTPase balance.

20 Article Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. 2015

Madhavan, Bindhu / Yue, Shijing / Galli, Uwe / Rana, Sanyukta / Gross, Wolfgang / Müller, Miryam / Giese, Nathalia A / Kalthoff, Holger / Becker, Thomas / Büchler, Markus W / Zöller, Margot. ·Tumor Cell Biology, General Surgery, University of Heidelberg, Heidelberg, Germany. ·Int J Cancer · Pubmed #25388097.

ABSTRACT: Late diagnosis contributes to pancreatic cancer (PaCa) dismal prognosis, urging for reliable, early detection. Serum-exosome protein and/or miRNA markers might be suitable candidates, which we controlled for patients with PaCa. Protein markers were selected according to expression in exosomes of PaCa cell line culture supernatants, but not healthy donors' serum-exosomes. miRNA was selected according to abundant recovery in microarrays of patients with PaCa, but not healthy donors' serum-exosomes and exosome-depleted serum. According to these preselections, serum-exosomes were tested by flow cytometry for the PaCa-initiating cell (PaCIC) markers CD44v6, Tspan8, EpCAM, MET and CD104. Serum-exosomes and exosome-depleted serum was tested for miR-1246, miR-4644, miR-3976 and miR-4306 recovery by qRT-PCR. The majority (95%) of patients with PaCa (131) and patients with nonPa-malignancies reacted with a panel of anti-CD44v6, -Tspan8, -EpCAM and -CD104. Serum-exosomes of healthy donors' and patients with nonmalignant diseases were not reactive. Recovery was tumor grading and staging independent including early stages. The selected miR-1246, miR-4644, miR-3976 and miR-4306 were significantly upregulated in 83% of PaCa serum-exosomes, but rarely in control groups. These miRNA were also elevated in exosome-depleted serum of patients with PaCa, but at a low level. Concomitant evaluation of PaCIC and miRNA serum-exosome marker panels significantly improved sensitivity (1.00, CI: 0.95-1) with a specificity of 0.80 (CI: 0.67-0.90) for PaCa versus all others groups and of 0.93 (CI: 0.81-0.98) excluding nonPa-malignancies. Thus, the concomitant evaluation of PaCIC and PaCa-related miRNA marker panels awaits retrospective analyses of larger cohorts, as it should allow for a highly sensitive, minimally-invasive PaCa diagnostics.

21 Article Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. 2014

Wolpin, Brian M / Rizzato, Cosmeri / Kraft, Peter / Kooperberg, Charles / Petersen, Gloria M / Wang, Zhaoming / Arslan, Alan A / Beane-Freeman, Laura / Bracci, Paige M / Buring, Julie / Canzian, Federico / Duell, Eric J / Gallinger, Steven / Giles, Graham G / Goodman, Gary E / Goodman, Phyllis J / Jacobs, Eric J / Kamineni, Aruna / Klein, Alison P / Kolonel, Laurence N / Kulke, Matthew H / Li, Donghui / Malats, Núria / Olson, Sara H / Risch, Harvey A / Sesso, Howard D / Visvanathan, Kala / White, Emily / Zheng, Wei / Abnet, Christian C / Albanes, Demetrius / Andreotti, Gabriella / Austin, Melissa A / Barfield, Richard / Basso, Daniela / Berndt, Sonja I / Boutron-Ruault, Marie-Christine / Brotzman, Michelle / Büchler, Markus W / Bueno-de-Mesquita, H Bas / Bugert, Peter / Burdette, Laurie / Campa, Daniele / Caporaso, Neil E / Capurso, Gabriele / Chung, Charles / Cotterchio, Michelle / Costello, Eithne / Elena, Joanne / Funel, Niccola / Gaziano, J Michael / Giese, Nathalia A / Giovannucci, Edward L / Goggins, Michael / Gorman, Megan J / Gross, Myron / Haiman, Christopher A / Hassan, Manal / Helzlsouer, Kathy J / Henderson, Brian E / Holly, Elizabeth A / Hu, Nan / Hunter, David J / Innocenti, Federico / Jenab, Mazda / Kaaks, Rudolf / Key, Timothy J / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Krogh, Vittorio / Kupcinskas, Juozas / Kurtz, Robert C / LaCroix, Andrea / Landi, Maria T / Landi, Stefano / Le Marchand, Loic / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Nakamura, Yusuke / Oberg, Ann L / Owzar, Kouros / Patel, Alpa V / Peeters, Petra H M / Peters, Ulrike / Pezzilli, Raffaele / Piepoli, Ada / Porta, Miquel / Real, Francisco X / Riboli, Elio / Rothman, Nathaniel / Scarpa, Aldo / Shu, Xiao-Ou / Silverman, Debra T / Soucek, Pavel / Sund, Malin / Talar-Wojnarowska, Renata / Taylor, Philip R / Theodoropoulos, George E / Thornquist, Mark / Tjønneland, Anne / Tobias, Geoffrey S / Trichopoulos, Dimitrios / Vodicka, Pavel / Wactawski-Wende, Jean / Wentzensen, Nicolas / Wu, Chen / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Hoover, Robert / Hartge, Patricia / Fuchs, Charles / Chanock, Stephen J / Stolzenberg-Solomon, Rachael S / Amundadottir, Laufey T. ·1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3]. · 1] Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2]. · 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. [3]. · 1] Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2]. · 1] Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. [2]. · 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. · 1] Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA. [2] Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. [3] New York University Cancer Institute, New York, New York, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. · 1] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · 1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. [3] Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA. · Group Health Research Institute, Seattle, Washington, USA. · 1] Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Epidemiology, Bloomberg School of Public Health, Baltimore, Maryland, USA. · The Cancer Research Center of Hawaii (retired), Honolulu, Hawaii, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. · 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. · 1] Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington, Seattle, Washington, USA. · 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA. [2] Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. · Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy. · 1] INSERM, Centre for Research in Epidemiology and Population Health (CESP), Nutrition, Hormones and Women's Health Team, Villejuif, France. [2] University Paris Sud, UMRS 1018, Villejuif, France. [3] Institut Gustave Roussy (IGR), Villejuif, France. · Westat, Rockville, Maryland, USA. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · 1] National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. [2] Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands. [3] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. · Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Württemberg-Hessen, Mannheim, Germany. · Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · 1] Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada. [2] Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, UK. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · 1] Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Massachusetts Veteran's Epidemiology, Research and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA. · 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. · 1] Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. [3] Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. · Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. · Preventive Medicine, University of Southern California, Los Angeles, California, USA. · Prevention and Research Center, Mercy Medical Center, Baltimore, Maryland, USA. · Cancer Prevention, University of Southern California, Los Angeles, California, USA. · 1] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard School of Public Health, Boston, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA. · The University of North Carolina Eshelman School of Pharmacy, Center for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, School of Medicine, Chapel Hill, North Carolina, USA. · International Agency for Research on Cancer, Lyon, France. · Cancer Epidemiology Unit, University of Oxford, Oxford, UK. · School of Clinical Medicine, University of Cambridge, Cambridge, UK. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA. · 1] Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. [2] Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain. [3] Department of Nutrition, National School of Public Health, Athens, Greece. · Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Biology, University of Pisa, Pisa, Italy. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. · Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy. · Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. · 1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. · Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. · Alliance Statistics and Data Center, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Alliance Statistics and Data Center, Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA. · 1] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · Department of Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Department of Gastroenterology, Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo, Italy. · 1] Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain. [2] Department of Epidemiology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. [3] CIBERESP, Madrid, Spain. · 1] Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. [2] Departament de Ciències i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Toxicogenomics Unit, Center for Toxicology and Safety, National Institute of Public Health, Prague, Czech Republic. · Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland. · 1st Propaideutic Surgical Department, Hippocration University Hospital, Athens, Greece. · Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. · 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. [3] Hellenic Health Foundation, Athens, Greece. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic. · Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA. · Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. · 1] Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. [2] New York University Cancer Institute, New York, New York, USA. · 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2]. · 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [3]. · 1] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. [2] Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. [3]. ·Nat Genet · Pubmed #25086665.

ABSTRACT: We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

22 Article Chondroitin sulfate proteoglycan CSPG4 as a novel hypoxia-sensitive marker in pancreatic tumors. 2014

Keleg, Shereen / Titov, Alexandr / Heller, Anette / Giese, Thomas / Tjaden, Christine / Ahmad, Sufian S / Gaida, Matthias M / Bauer, Andrea S / Werner, Jens / Giese, Nathalia A. ·European Pancreas Centre, Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Department of Functional Genomics, German Cancer Research Centre, Heidelberg, Germany. ·PLoS One · Pubmed #24932730.

ABSTRACT: CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissue(high)/sera(low)-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial lineage and contribute to cell polarity disorders. Surficial retention on tumor cells renders CSPG4 an attractive therapeutic target. Systemic 'drop and restoration' alterations accompanying IPMN and PDAC progression indicate that the interference of pancreatic diseases with local and remote shedding/release of sCSPG4 into circulation deserves broad diagnostic exploration.

23 Article Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer. 2014

Hartmann, Natalie / Giese, Nathalia A / Giese, Thomas / Poschke, Isabel / Offringa, Rienk / Werner, Jens / Ryschich, Eduard. ·Authors' Affiliations: Departments of General Surgery and. · Immunology, University of Heidelberg; and. · Department of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany. · Authors' Affiliations: Departments of General Surgery and eduard.ryschich@med.uni-heidelberg.de. ·Clin Cancer Res · Pubmed #24763614.

ABSTRACT: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive collagen-rich stroma. T cells that infiltrate pancreatic cancers frequently become trapped in the stroma and do not contact tumor cells. Here, we aimed to analyze how chemokines and extracellular matrix (ECM) collagen interact in mediating T-cell infiltration in PDAC. EXPERIMENTAL DESIGN: T-cell distribution and ECM structure within tumors were analyzed. Chemokine concentrations in human PDAC were compared with the levels of immune cell infiltration. We assessed the influences of selected chemokines and collagen on directed and random T-cell movement using in vitro migration systems. RESULTS: PDAC overproduced several T-cell-active chemokines, but their levels were not correlated with intratumoral T-cell infiltration. In the absence of collagen, directed migration of activated T cells was induced by chemokines. Interestingly, collagen itself promoted high migratory activity of T cells, but completely abolished chemokine-guided movement. This effect was not altered by a β1-integrin blocking antibody. Activated T cells actively migrated in low-density collagen matrices, but migration was inhibited in dense collagen. Accordingly, T cells were heterogeneously distributed in the pancreatic cancer stroma, with the majority residing in areas of low-density collagen far from tumor clusters. CONCLUSION: The excessive desmoplasia in PDAC promotes T-cell migration by contact guidance, which abrogates tumor cell-directed movement. Furthermore, dense collagen networks represent a physical barrier, additionally rearranging T-cell distribution to favor tumor stroma. These mechanisms are mainly responsible for intrastromal T-cell trapping in pancreatic cancer and may hinder the development of T-cell-based immunotherapies.

24 Article Sulforaphane counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication. 2014

Forster, Tobias / Rausch, Vanessa / Zhang, Yiyao / Isayev, Orkhan / Heilmann, Katharina / Schoensiegel, Frank / Liu, Li / Nessling, Michelle / Richter, Karsten / Labsch, Sabrina / Nwaeburu, Clifford C / Mattern, Juergen / Gladkich, Jury / Giese, Nathalia / Werner, Jens / Schemmer, Peter / Gross, Wolfgang / Gebhard, Martha M / Gerhauser, Clarissa / Schaefer, Michael / Herr, Ingrid. ·General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. ·Oncotarget · Pubmed #24742583.

ABSTRACT: The extreme aggressiveness of pancreatic ductal adenocarcinoma (PDA) has been associated with blocked gap junctional intercellular communication (GJIC) and the presence of cancer stem cells (CSCs). We examined whether disturbed GJIC is responsible for a CSC phenotype in established and primary cancer cells and patient tissue of PDA using interdisciplinary methods based in physiology, cell and molecular biology, histology and epigenetics. Flux of fluorescent dyes and gemcitabine through gap junctions (GJs) was intact in less aggressive cells but not in highly malignant cells with morphological dysfunctional GJs. Among several connexins, only Cx43 was expressed on the cell surface of less aggressive and GJIC-competent cells, whereas Cx43 surface expression was absent in highly malignant, E-cadherin-negative and GJIC-incompetent cells. The levels of total Cx43 protein and Cx43 phosphorylated at Ser368 and Ser279/282 were high in normal tissue but low to absent in malignant tissue. si-RNA-mediated inhibition of Cx43 expression in GJIC-competent cells prevented GJIC and induced colony formation and the expression of stem cell-related factors. The bioactive substance sulforaphane enhanced Cx43 and E-cadherin levels, inhibited the CSC markers c-Met and CD133, improved the functional morphology of GJs and enhanced GJIC. Sulforaphane altered the phosphorylation of several kinases and their substrates and inhibition of GSK3, JNK and PKC prevented sulforaphane-induced CX43 expression. The sulforaphane-mediated expression of Cx43 was not correlated with enhanced Cx43 RNA expression, acetylated histone binding and Cx43 promoter de-methylation, suggesting that posttranslational phosphorylation is the dominant regulatory mechanism. Together, the absence of Cx43 prevents GJIC and enhances aggressiveness, whereas sulforaphane counteracts this process, and our findings highlight dietary co-treatment as a viable treatment option for PDA.

25 Article Combined inhibition of Notch and JAK/STAT is superior to monotherapies and impairs pancreatic cancer progression. 2014

Palagani, Vindhya / Bozko, Przemyslaw / El Khatib, Mona / Belahmer, Hanane / Giese, Nathalia / Sipos, Bence / Malek, Nisar P / Plentz, Ruben R. ·Department of Internal Medicine I, Medical University Hospital, 72076 Tuebingen , Germany. ·Carcinogenesis · Pubmed #24293409.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that Notch and janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathways are both important for the initiation and progression of PDAC. The purpose of this study was to determine the outcome of targeting these two tumor signaling pathways simultaneously both in vitro and in vivo. We assessed the combinational effects of the γ-secretase inhibitor IX (GSI IX) and JAK2 inhibitor (AG-490) on growth and epithelial plasticity of human pancreatic cancer cell lines, and in a genetically engineered mouse model (Pdx1-Cre, LSL-KrasG12D, p53(lox/+)) of PDAC. Dual treatment with GSI IX and AG-490 significantly impaired cell proliferation, migration, invasion, soft agar growth and apoptosis when compared with monotherapies. Most importantly, combinational treatment significantly attenuates tumor progression in vivo and suppresses conversion from acinar-ductal-metaplasia to PDAC. Our results suggest that targeting Notch and JAK2/STAT3 signaling pathways simultaneously is superior to single inhibitions, supporting combined treatment by GSI IX and AG-490 as a potential therapeutic approach for PDAC. However, the study design limits the direct transfer into the clinic and the impact of dual treatment in patients with PDAC remains still to be determined.

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