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Pancreatic Neoplasms: HELP
Articles by Stephan A. Hahn
Based on 18 articles published since 2010
(Why 18 articles?)

Between 2010 and 2020, S. A. Hahn wrote the following 18 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
1 Review A genetic roadmap of pancreatic cancer: still evolving. 2017

Notta, Faiyaz / Hahn, Stephan A / Real, Francisco X. ·Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Canada. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. · CIBERONC, Madrid, Spain. ·Gut · Pubmed #28993418.

ABSTRACT: A diagnosis of pancreatic ductal adenocarcinoma (PDA) is often fatal. PDA is widely recognised as one of the 'incurable cancers' because therapies against this tumour type are generally ineffective. The fatal nature of this tumour is due to its aggressive clinical course. Pancreatic cancer commonly presents at the metastatic stage; even in cases where tumours are localised to the pancreas at diagnosis, metastatic seeds have often been invariably been spawned off, frustrating surgical attempts to cure the cancer. The key principles of pancreatic cancer mutational development were outlined nearly two decades ago using the genetics of precursor lesions to position the various stages of tumour progression. Since then, there has been a cavalcade of new data. How these recent studies impact the classical perceptions of pancreatic cancer development is a work in progress. Given that significant improvements in patient outcomes are not in sight for this disease, it is likely that broadening the current perspectives and acquiring deeper biological insights into the morphogenetic route of tumour development will be needed to foster new strategies for more effective cancer control.

2 Article A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling. 2016

Kong, Bo / Wu, Weiwei / Cheng, Tao / Schlitter, Anna Melissa / Qian, Chengjia / Bruns, Philipp / Jian, Ziying / Jäger, Carsten / Regel, Ivonne / Raulefs, Susanne / Behler, Nora / Irmler, Martin / Beckers, Johannes / Friess, Helmut / Erkan, Mert / Siveke, Jens T / Tannapfel, Andrea / Hahn, Stephan A / Theis, Fabian J / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Department of Surgery, Technische Universität München (TUM), Munich, Germany Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany. · Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany. · Institute of Experimental Genetics (IEG), Helmholtz-Zentrum München, Munich, Germany Technische Universität München, Chair of Experimental Genetics, Freising, Germany Deutsches Zentrum für Diabetesforschung (DZD), Neuherberg, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Gastroenterology, TUM, Munich, Germany. · Institute of Pathology, Ruhr-University Bochum, Bochum, Germany. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Institute of Computational Biology, Helmholtz-Zentrum München, Munich, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Gut · Pubmed #25601637.

ABSTRACT: OBJECTIVE: Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. DESIGN: We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. RESULTS: Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. CONCLUSIONS: These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.

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

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

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

4 Article New insights in the composition of extracellular vesicles from pancreatic cancer cells: implications for biomarkers and functions. 2014

Klein-Scory, Susanne / Tehrani, Mahnaz Moradian / Eilert-Micus, Christina / Adamczyk, Kamila A / Wojtalewicz, Nathalie / Schnölzer, Martina / Hahn, Stephan A / Schmiegel, Wolff / Schwarte-Waldhoff, Irmgard. ·IMBL, Medical Clinic Knappschaftskrankenhaus Bochum GmbH, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany. · Functional Proteome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. · Molecular Gastrointestinal Oncology MGO, Ruhr-University Bochum, Universitätsstraße 150, 44780 Bochum, Germany. · IMBL, Medical Clinic Knappschaftskrankenhaus Bochum GmbH, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany ; Medical Department, Medical Clinic Knappschaftskrankenhaus Bochum GmbH, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany. ·Proteome Sci · Pubmed #25469109.

ABSTRACT: BACKGROUND: Pancreatic cancer development is associated with characteristic alterations like desmoplastic reaction and immune escape which are mediated by the cell-cell communication mechanism and by the microenvironment of the cells. The whole of released components are important determinants in these processes. Especially the extracellular vesicles released by pancreatic cancer cells play a role in cell communication and modulate cell growth and immune responses. RESULTS: Here, we present the proteomic description of affinity purified extracellular vesicles from pancreatic tumour cells, compared to the secretome, defined as the whole of the proteins released by pancreatic cancer cells. The proteomic data provide comprehensive catalogues of hundreds of proteins, and the comparison reveals a special proteomic composition of pancreatic cancer cell derived extracellular vesicles. The functional analysis of the protein composition displayed that membrane proteins, glycoproteins, small GTP binding proteins and a further, heterogeneous group of proteins are enriched in vesicles, whereas proteins derived from proteasomes and ribosomes, as well as metabolic enzymes, are not components of the vesicles. Furthermore proteins playing a role in carcinogenesis and modulators of the extracellular matrix (ECM) or cell-cell interactions are components of affinity purified extracellular vesicles. CONCLUSION: The data deepen the knowledge of extracellular vesicle composition by hundreds of proteins that have not been previously described as vesicle components released by pancreatic cancer cells. Extracellular vesicles derived from pancreatic cancer cells show common proteins shared with other vesicles as well as cell type specific proteins indicating biomarker candidates and suggesting functional roles in cancer cell stroma interactions.

5 Article Induction of pancreatic cancer cell migration by an autocrine epidermal growth factor receptor activation. 2014

Stock, Anna-Maria / Hahn, Stephan A / Troost, Gabriele / Niggemann, Bernd / Zänker, Kurt S / Entschladen, Frank. ·Institute of Immunology and Experimental Oncology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany. · Department of Molecular Gastroenterological Oncology, Centre of Clinical Research, Ruhr-University of Bochum, 44780 Bochum, Germany. · Institute of Immunology and Experimental Oncology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany. Electronic address: entschladen@uni-wh.de. ·Exp Cell Res · Pubmed #24810090.

ABSTRACT: Pancreatic cancer is characterized by aggressive local invasion and early metastasis formation. Active migration of the pancreatic cancer cells is essential for these processes. We have shown previously that the pancreatic cancer cells lines CFPAC1 and IMIM-PC2 show high migratory activity, and we have investigated herein the reason for this observation. Cell migration was assessed using a three-dimensional, collagen-based assay and computer-assisted cell tracking. The expression of receptor tyrosine kinases was determined by flow-cytometry and cytokine release was measured by an enzyme-linked immunoassay. Receptor function was blocked by antibodies or pharmacological enzyme inhibitors. Both cells lines express the epidermal growth factor receptor (EGFR) as well as its family-member ErbB2 and the platelet-derived growth factor receptor (PDGFR)α, whereas only weak expression was detected for ErbB3 and no expression of PDGFRβ. Pharmacological inhibition of the EGFR or ErbB2 significantly reduced the migratory activity in both cell lines, as did an anti-EGFR antibody. Interestingly, combination of the latter with an anti-PDGFR antibody led to an even more pronounced reduction. Both cell lines release detectable amounts of EGF. Thus, the high migratory activity of the investigated pancreatic cancer cell lines is due to autocrine EGFR activation and possibly of other receptor tyrosine kinases.

6 Article A microRNA-based test improves endoscopic ultrasound-guided cytologic diagnosis of pancreatic cancer. 2014

Brand, Randall E / Adai, Alex T / Centeno, Barbara A / Lee, Linda S / Rateb, George / Vignesh, Shivakumar / Menard, Charles / Wiechowska-Kozłowska, Anna / Bołdys, Hubert / Hartleb, Marek / Sanders, Michael K / Munding, Johanna B / Tannapfel, Andrea / Hahn, Stephan A / Stefańczyk, Ludomir / Tsongalis, Gregory J / Whitcomb, David C / Conwell, Darwin L / Morisset, Jean A / Gardner, Timothy B / Gordon, Stuart R / Suriawinata, Arief A / Lloyd, Maura B / Wylie, Dennis / Labourier, Emmanuel / Andruss, Bernard F / Szafranska-Schwarzbach, Anna E. ·Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Asuragen, Inc, Austin, Texas. · Department of Pathology and Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. · Center for Pancreatic Disease, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Medicine, Division of Gastroenterology, University of Sherbrooke, Fleurimont, Quebec, Canada. · Department of Endoscopy, Hospital of the Ministry of Internal Affairs and Administration, Szczecin, Poland. · Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland. · Institute of Pathology, Ruhr-University of Bochum, Bochum, Germany. · Molecular GI-Oncology and Department of Pathology, Ruhr-University of Bochum, Bochum, Germany. · Department of Medicine, Division of Radiology, Medical University of Łódź, Łódz, Poland. · Department of Pathology and Department of Gasteroenterology and Hepatology, Dartmouth Hitchcock Medical Center and The Audrey and Theodor Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. · Asuragen, Inc, Austin, Texas. Electronic address: aschwarzbach@asuragen.com. ·Clin Gastroenterol Hepatol · Pubmed #24662333.

ABSTRACT: BACKGROUND & AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in combination with cytopathology is the optimal method for diagnosis and staging of pancreatic ductal adenocarcinoma (PDAC) and other pancreatic lesions. Its clinical utility, however, can be limited by high rates of indeterminate or false-negative results. We aimed to develop and validate a microRNA (miRNA)-based test to improve preoperative detection of PDAC. METHODS: Levels of miRNAs were analyzed in a centralized clinical laboratory by relative quantitative polymerase chain reaction in 95 formalin-fixed paraffin-embedded specimens and 228 samples collected by EUS-FNA during routine evaluations of patients with solid pancreatic masses at 4 institutions in the United States, 1 in Canada, and 1 in Poland. RESULTS: We developed a 5-miRNA expression classifier, consisting of MIR24, MIR130B, MIR135B, MIR148A, and MIR196, that could identify PDAC in well-characterized, formalin-fixed, paraffin-embedded specimens. Detection of PDAC in EUS-FNA samples increased from 78.8% by cytology analysis alone (95% confidence interval, 72.2%-84.5%) to 90.8% when combined with miRNA analysis (95% confidence interval, 85.6%-94.5%). The miRNA classifier correctly identified 22 additional true PDAC cases among 39 samples initially classified as benign, indeterminate, or nondiagnostic by cytology. Cytology and miRNA test results each were associated significantly with PDAC (P < .001), with positive predictive values greater than 99% (95% confidence interval, 96%-100%). CONCLUSIONS: We developed and validated a 5-miRNA classifier that can accurately predict which preoperative pancreatic EUS-FNA specimens contain PDAC. This test might aid in the diagnosis of pancreatic cancer by reducing the number of FNAs without a definitive adenocarcinoma diagnosis, thereby reducing the number of repeat EUS-FNA procedures.

7 Article The pancreatic expression database: recent extensions and updates. 2014

Dayem Ullah, Abu Z / Cutts, Rosalind J / Ghetia, Millika / Gadaleta, Emanuela / Hahn, Stephan A / Crnogorac-Jurcevic, Tatjana / Lemoine, Nicholas R / Chelala, Claude. ·Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK and Molecular GI-Onkologie (MGO), University of Bochum, Germany. ·Nucleic Acids Res · Pubmed #24163255.

ABSTRACT: The Pancreatic Expression Database (PED, http://www.pancreasexpression.org) is the only device currently available for mining of pancreatic cancer literature data. It brings together the largest collection of multidimensional pancreatic data from the literature including genomic, proteomic, microRNA, methylomic and transcriptomic profiles. PED allows the user to ask specific questions on the observed levels of deregulation among a broad range of specimen/experimental types including healthy/patient tissue and body fluid specimens, cell lines and murine models as well as related treatments/drugs data. Here we provide an update to PED, which has been previously featured in the Database issue of this journal. Briefly, PED data content has been substantially increased and expanded to cover methylomics studies. We introduced an extensive controlled vocabulary that records specific details on the samples and added data from large-scale meta-analysis studies. The web interface has been improved/redesigned with a quick search option to rapidly extract information about a gene/protein of interest and an upload option allowing users to add their own data to PED. We added a user guide and implemented integrated graphical tools to overlay and visualize retrieved information. Interoperability with biomart-compatible data sets was significantly improved to allow integrative queries with pancreatic cancer data.

8 Article Multimodal Treatment Eliminates Cancer Stem Cells and Leads to Long-Term Survival in Primary Human Pancreatic Cancer Tissue Xenografts. 2013

Hermann, Patrick C / Trabulo, Sara M / Sainz, Bruno / Balic, Anamaria / Garcia, Elena / Hahn, Stephan A / Vandana, Mallaredy / Sahoo, Sanjeeb K / Tunici, Patrizia / Bakker, Annette / Hidalgo, Manuel / Heeschen, Christopher. ·Stem Cells and Cancer Group, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ·PLoS One · Pubmed #23825539.

ABSTRACT: PURPOSE: In spite of intense research efforts, pancreatic ductal adenocarcinoma remains one of the most deadly malignancies in the world. We and others have previously identified a subpopulation of pancreatic cancer stem cells within the tumor as a critical therapeutic target and additionally shown that the tumor stroma represents not only a restrictive barrier for successful drug delivery, but also serves as a paracrine niche for cancer stem cells. Therefore, we embarked on a large-scale investigation on the effects of combining chemotherapy, hedgehog pathway inhibition, and mTOR inhibition in a preclinical mouse model of pancreatic cancer. EXPERIMENTAL DESIGN: Prospective and randomized testing in a set of almost 200 subcutaneous and orthotopic implanted whole-tissue primary human tumor xenografts. RESULTS: The combined targeting of highly chemoresistant cancer stem cells as well as their more differentiated progenies, together with abrogation of the tumor microenvironment by targeting the stroma and enhancing tissue penetration of the chemotherapeutic agent translated into significantly prolonged survival in preclinical models of human pancreatic cancer. Most pronounced therapeutic effects were observed in gemcitabine-resistant patient-derived tumors. Intriguingly, the proposed triple therapy approach could be further enhanced by using a PEGylated formulation of gemcitabine, which significantly increased its bioavailability and tissue penetration, resulting in a further improved overall outcome. CONCLUSIONS: This multimodal therapeutic strategy should be further explored in the clinical setting as its success may eventually improve the poor prognosis of patients with pancreatic ductal adenocarcinoma.

9 Article Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. 2013

Zimmermann, Gunther / Papke, Björn / Ismail, Shehab / Vartak, Nachiket / Chandra, Anchal / Hoffmann, Maike / Hahn, Stephan A / Triola, Gemma / Wittinghofer, Alfred / Bastiaens, Philippe I H / Waldmann, Herbert. ·Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany. ·Nature · Pubmed #23698361.

ABSTRACT: The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEδ interaction that selectively bind to the prenyl-binding pocket of PDEδ with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.

10 Article Norepinephrine inhibits the migratory activity of pancreatic cancer cells. 2013

Stock, Anna-Maria / Powe, Desmond G / Hahn, Stephan A / Troost, Gabriele / Niggemann, Bernd / Zänker, Kurt S / Entschladen, Frank. ·Institute of Immunology and Experimental Oncology, Centre for Biomedical Education and Research ZBAF, Witten/Herdecke University, 58448 Witten, Germany. ·Exp Cell Res · Pubmed #23639786.

ABSTRACT: We have shown previously that norepinephrine induces migratory activity of tumour cells from breast, colon and prostate tissue via activation of beta-2 adrenergic receptors. Consequently, this effect can be inhibited pharmacologically by clinically established beta-blockers. Tumour cell migration is a prerequisite for metastasis formation, and accordingly we and others have shown that breast cancer patients, which take beta-blockers due to hypertension, have reduced metastasis formation and increased survival probability as compared to patients without hypertension or using other anti-hypertensive medication. Unlike the aforementioned tumour cells, pancreatic cancer cells show a reduced migratory activity upon norepinephrine treatment. By means of our three-dimensional, collagen-based cell migration assay, we have investigated the signal transduction pathways involved in this phenomenon. We have found that this conflicting effect of norepinephrine on pancreatic cancer cells is due to an imbalanced activation of the two pathways that usually mediate a pro-migratory effect of norepinephrine in other tumour cell types. Firstly, the inhibitory effect results from activation of a pathway which causes a strong increase of the secondary cell signalling molecule, cAMP. In addition, activation of phospholipase C gamma and the downstream protein kinase C alpha were shown to be already activated in pancreatic cancer cells and cannot be further activated by norepinephrine. We hypothesize that this constitutive activation of the phospholipase C gamma pathway is due to a cross-talk with receptor tyrosine kinase signalling, and this might also deliver an explanation for the unusual high spontaneous migratory activity of pancreatic cancer cells.

11 Article Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for pancreatic and colorectal adenocarcinoma. 2013

Baraniskin, Alexander / Nöpel-Dünnebacke, Stefanie / Ahrens, Maike / Jensen, Steffen Grann / Zöllner, Hannah / Maghnouj, Abdelouahid / Wos, Alexandra / Mayerle, Julia / Munding, Johanna / Kost, Dennis / Reinacher-Schick, Anke / Liffers, Sven / Schroers, Roland / Chromik, Ansgar M / Meyer, Helmut E / Uhl, Waldemar / Klein-Scory, Susanne / Weiss, Frank U / Stephan, Christian / Schwarte-Waldhoff, Irmgard / Lerch, Markus M / Tannapfel, Andrea / Schmiegel, Wolff / Andersen, Claus Lindbjerg / Hahn, Stephan A. ·Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. ·Int J Cancer · Pubmed #22907602.

ABSTRACT: Improved non-invasive strategies for early cancer detection are urgently needed to reduce morbidity and mortality. Non-coding RNAs, such as microRNAs and small nucleolar RNAs, have been proposed as biomarkers for non-invasive cancer diagnosis. Analyzing serum derived from nude mice implanted with primary human pancreatic ductal adenocarcinoma (PDAC), we identified 15 diagnostic microRNA candidates. Of those miR-1246 was selected based on its high abundance in serum of tumor carrying mice. Subsequently, we noted a cross reactivity of the established miR-1246 assays with RNA fragments derived from U2 small nuclear RNA (RNU2-1). Importantly, we found that the assay signal discriminating tumor from controls was derived from U2 small nuclear RNA (snRNA) fragments (RNU2-1f) and not from miR-1246. In addition, we observed a remarkable stability of RNU2-1f in serum and provide experimental evidence that hsa-miR-1246 is likely a pseudo microRNA. In a next step, RNU2-1f was measured by qRT-PCR and normalized to cel-54 in 191 serum/plasma samples from PDAC and colorectal carcinoma (CRC) patients. In comparison to 129 controls, we were able to classify samples as cancerous with a sensitivity and specificity of 97.7% [95% CI = (87.7, 99.9)] and 90.6% [95% CI = (80.7, 96.5)], respectively [area under the ROC curve 0.972]. Of note, patients with CRC were detected with our assay as early as UICC Stage II with a sensitivity of 81%. In conclusion, this is the first report showing that fragments of U2 snRNA are highly stable in serum and plasma and may serve as novel diagnostic biomarker for PDAC and CRC for future prospective screening studies.

12 Article Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions. 2013

Neesse, Albrecht / Hahnenkamp, Anke / Griesmann, Heidi / Buchholz, Malte / Hahn, Stefan A / Maghnouj, Abdelouahid / Fendrich, Volker / Ring, Janine / Sipos, Bence / Tuveson, David A / Bremer, Christoph / Gress, Thomas M / Michl, Patrick. ·Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Marburg, Germany. ·Gut · Pubmed #22677720.

ABSTRACT: OBJECTIVES: Novel imaging methods based on specific molecular targets to detect both established neoplasms and their precursor lesions are highly desirable in cancer medicine. Previously, we identified claudin-4, an integral constituent of tight junctions, as highly expressed in various gastrointestinal tumours including pancreatic cancer. Here, we investigate the potential of targeting claudin-4 with a naturally occurring ligand to visualise pancreatic cancer and its precursor lesions in vitro and in vivo by near-infrared imaging approaches. DESIGN: A non-toxic C-terminal fragment of the claudin-4 ligand Clostridium perfringens enterotoxin (C-CPE) was labelled with a cyanine dye (Cy5.5). Binding of the optical tracer was analysed on claudin-4 positive and negative cells in vitro, and tumour xenografts in vivo. In addition, two genetically engineered mouse models for pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer were used for in vivo validation. Optical imaging studies were conducted using 2D planar fluorescence reflectance imaging (FRI) technology and 3D fluorescence-mediated tomography (FMT). RESULTS: In vitro, the peptide-dye conjugate showed high binding affinity to claudin-4 positive CAPAN1 cells, while claudin-4 negative HT1080 cells revealed little or no fluorescence. In vivo, claudin-4 positive tumour xenografts, endogenous pancreatic tumours, hepatic metastases, as well as preinvasive PanIN lesions, were visualised by FRI and FMT up to 48 h after injection showing a significantly higher average of fluorochrome concentration as compared with claudin-4 negative xenografts and normal pancreatic tissue. CONCLUSIONS: C-CPE-Cy5.5 combined with novel optical imaging methods enables non-invasive visualisation of claudin-4 positive murine pancreatic tumours and their precursor lesions, representing a promising modality for early diagnostic imaging.

13 Article Lack of CCR7 expression is rate limiting for lymphatic spread of pancreatic ductal adenocarcinoma. 2012

Sperveslage, Jan / Frank, Sunna / Heneweer, Carola / Egberts, Jan / Schniewind, Bodo / Buchholz, Malte / Bergmann, Frank / Giese, Nathalia / Munding, Johanna / Hahn, Stephan A / Kalthoff, Holger / Klöppel, Günter / Sipos, Bence. ·Institute of Pathology, University of Tübingen, Tübingen, Germany. ·Int J Cancer · Pubmed #22020953.

ABSTRACT: CCR7 expression on tumor cells promotes lymphatic spread in several malignant tumors. However, a comprehensive characterization of the CCL19/CCL21-CCR7 axis in pancreatic ductal adenocarcinoma (PDAC), which is known for its high rates of lymph-node metastases, is still lacking. CCR7 mRNA and CCR7 protein were found to be expressed in spheroid cultures of all six examined PDAC cell lines. In migration assays, CCR7 expressing PDAC cells showed enhanced migration toward CCL19 and CCL21, the two ligands of CCR7. In an orthotopic nude mouse model, CCR7-transfected PT45P1 cells gave rise to significantly larger tumors and showed a higher frequency of lymph vessel invasion and lymph-node metastases than mock-transfected cells. In an analysis using quantitative real-time PCR, CCR7 showed fourfold overexpression in microdissected PDAC cells compared to normal duct cells. Moderate-to-strong immunohistochemical CCR7 expression, found in 58 of 121 well-characterized human PDACs, correlated with high rates of lymph vessel invasion. Conversely, PDACs completely lacking CCR7 expression showed only low rates of lymph vessel invasion and lymph-node metastases. The evaluation of CCL21 expression by immunofluorescence staining revealed a significant upregulation of CCL21 in peritumoral and intratumoral lymph vessels compared to lymph vessels in disease-free pancreata. In conclusion, our study revealed strong evidence that lack of CCR7 impairs the metastatic potential of PDAC. Lymph vessel invasion by CCR7 expressing PDAC cells may be additionally enhanced by upregulation of CCL21 in tumor-associated lymph vessels, representing a previously unknown factor of lymphatic spread.

14 Article Global microRNA expression profiling of microdissected tissues identifies miR-135b as a novel biomarker for pancreatic ductal adenocarcinoma. 2012

Munding, Johanna B / Adai, Alex T / Maghnouj, Abdelouahid / Urbanik, Aleksandra / Zöllner, Hannah / Liffers, Sven T / Chromik, Ansgar M / Uhl, Waldemar / Szafranska-Schwarzbach, Anna E / Tannapfel, Andrea / Hahn, Stephan A. ·Institute of Pathology, Ruhr-University Bochum, Bochum, Germany. ·Int J Cancer · Pubmed #21953293.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is known for its poor prognosis resulting from being diagnosed at an advanced stage. Accurate early diagnosis and new therapeutic modalities are therefore urgently needed. MicroRNAs (miRNAs), considered a new class of biomarkers and therapeutic targets, may be able to fulfill those needs. Combining tissue microdissection with global miRNA array analyses, cell type-specific miRNA expression profiles were generated for normal pancreatic ductal cells, acinar cells, PDAC cells derived from xenografts and also from macrodissected chronic pancreatitis (CP) tissues. We identified 78 miRNAs differentially expressed between ND and PDAC cells providing new insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development. Having filtered miRNAs which are upregulated in the three pairwise comparisons of PDAC vs. ND, PDAC vs. AZ and PDAC vs. CP, we identified 15 miRNA biomarker candidates including miR-135b. Using relative qRT-PCR to measure miR-135b normalized to miR-24 in 75 FFPE specimens (42 PDAC and 33 CP) covering a broad range of tumor content, we discriminated CP from PDAC with a sensitivity and specificity of 92.9% [95% CI=(80.5, 98.5)] and 93.4% [95% CI=(79.8, 99.3)], respectively. Furthermore, the area under the curve (AUC) value reached of 0.97 was accompanied by positive and negative predictive values of 95% and 91%, respectively. In conclusion, we report pancreatic cell-specific global miRNA profiles, which offer new candidate miRNAs to be exploited for functional studies in PDAC. Furthermore, we provide evidence that miRNAs are well-suited analytes for development of sensitive and specific aid-in-diagnosis tests for PDAC.

15 Article MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting CDC25B. 2011

Liffers, Sven-T / Munding, Johanna B / Vogt, Markus / Kuhlmann, Jan D / Verdoodt, Berlinda / Nambiar, Sandeep / Maghnouj, Abdelouahid / Mirmohammadsadegh, Alireza / Hahn, Stephan A / Tannapfel, Andrea. ·Institute of Pathology, Ruhr-University Bochum, Bochum, Germany. ·Lab Invest · Pubmed #21709669.

ABSTRACT: MicroRNAs (miRNAs: short non-coding RNAs) are emerging as a class of potential novel tumor markers, as their dysregulation is being increasingly reported in various types of cancers. In the present study, we investigated the transcription status of miRNA-148a (miR-148a) in human pancreatic ductal adenocarcinoma (PDAC) and its role in the regulation of the dual specificity protein phosphatase CDC25B. We observed that miR-148a exhibited a significant 4-fold down-regulation in PDAC as opposed to normal pancreatic ductal cells. In addition, we observed that stable lentiviral-mediated overexpression of miR-148a in the pancreatic cancer cell line IMIM-PC2, inhibited tumor cell growth and colony formation. Furthermore, CDC25B was identified as a potential target of miR-148a by in silico analysis using PicTar, Targetscan and miRanda in conjunction with gene ontology analysis. The proposed interaction between miR-148a and the 3' untranslated region (UTR) of CDC25B was verified by in-vitro luciferase assays. We demonstrate that the activity of a luciferase reporter containing the 3'UTR of CDC25B was repressed in the presence of miR-148a mimics, confirming that miR-148a targets the 3'UTR of CDC25B. Finally, CDC25B was down-regulated at the protein level in miR-148a overexpressing IMIM-PC2-cells, and in transiently transfected pancreatic cell lines (as detected by Western blot analysis), as well as in patient tumor samples (as detected by immunohistochemistry). In summary, we identified CDC25B as a novel miR-148a target which may confer a proliferative advantage in PDAC.

16 Article The Pancreatic Expression database: 2011 update. 2011

Cutts, Rosalind J / Gadaleta, Emanuela / Hahn, Stephan A / Crnogorac-Jurcevic, Tatjana / Lemoine, Nicholas R / Chelala, Claude. ·Centre for Molecular Oncology and Imaging, Institute of Cancer and CR-UK Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. ·Nucleic Acids Res · Pubmed #20959292.

ABSTRACT: The Pancreatic Expression database (PED, http://www.pancreasexpression.org) has established itself as the main repository for pancreatic-derived -omics data. For the past 3 years, its data content and access have increased substantially. Here we describe several of its new and improved features, such as data content, which now includes over 60,000 measurements derived from transcriptomics, proteomics, genomics and miRNA profiles from various pancreas-centred reports on a broad range of specimen and experimental types. We also illustrate the capabilities of its interface, which allows integrative queries that can combine PED data with a growing number of biological resources such as NCBI, Ensembl, UniProt and Reactome. Thus, PED is capable of retrieving and integrating different types of -omics, annotations and clinical data. We also focus on the importance of data sharing and interoperability in the cancer field, and the integration of PED into the International Cancer Genome Consortium (ICGC) data portal.

17 Article Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families. 2010

Slater, Emily P / Langer, Peter / Fendrich, Volker / Habbe, Nils / Chaloupka, Brunhilde / Matthäi, Elvira / Sina, Mercedes / Hahn, Stephan A / Bartsch, Detlef K. ·Department of Visceral-, Thoracic and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany. slater@med.uni-marburg.de ·Fam Cancer · Pubmed #20195775.

ABSTRACT: Previous small scale studies reported that deleterious BRCA2 and CDKN2a germline mutations contribute to a subset of families with inherited pancreatic cancer. As the prevalence of those mutations in the setting of familial pancreatic cancer is still not well defined for the German population, we evaluated the presence of BRCA2 and CDKN2a germline mutations in a large cohort of familial pancreatic cancer (FPC) families from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Fifty-six FPC families with at least two-first-degree relatives with confirmed pancreatic cancer that did not fulfill the criteria of other tumor predisposition syndromes, were analyzed for BRCA2 and CDKN2a germline mutations by DHPLC and/or direct sequencing. No deleterious CDKN2a mutations were identified in our families suggesting that CDKN2a mutations are unlikely to predispose PC in FPC families without melanoma. No deleterious BRCA2 mutations, but 6 unclassified variants, were detected in our FPC collection. Combining the prevalence of deleterious BRCA2 germline mutations from our previous separate study with the data from this study we were able to much more accurately estimate the BRCA2 carrier frequency for FPC families in the German population. A total of two mutations and 6 unclassified variants (mutation range: 2.8-11.4%) were thus identified in 70 German FPC families, indicating that the prevalence of BRCA2 mutations in the German FPC population is less frequent than previously reported.

18 Article Clinical and genetic analysis of 18 pancreatic carcinoma/melanoma-prone families. 2010

Bartsch, D K / Langer, P / Habbe, N / Matthäi, E / Chaloupka, B / Sina, M / Hahn, S A / Slater, E P. ·Department of Surgery, Philipps-University, Marburg, Germany. ·Clin Genet · Pubmed #20041885.

ABSTRACT: Families with both melanoma and pancreatic cancer are extremely rare and some are affected with the autosomal dominant inherited familial atypical multiple mole melanoma-pancreatic cancer (FAMMM-PC) syndrome. The phenotypic and genotypic expressions of such pancreatic cancer-melanoma prone families are not well defined. The National Case Collection of Familial Pancreatic Cancer of the Deutsche Krebshilfe includes 110 pancreatic cancer families, 18 of which (16%) show an association of pancreatic cancer and melanoma. These 18 families were analysed regarding their phenotype and the prevalence of germline mutations in the candidate genes CDKN2A, BRCA2, CHEK2, NOD2, ARL11 and Palladin (PALLD). There were two types of families: five families with the FAMMM-PC phenotype and 13 PC/melanoma families without the multiple mole phenotypes (PCMS). The prevalences of PC and melanoma in the two types of families were similar. The prevalence of other tumour types, especially breast carcinoma, was higher (11%) in PCMS- than in FAMMM-PC families (2.4%, p = 0.02). CDKN2A mutations were identified in 2 of 18 (11%) PCMS families. A cosegregating BRCA2 mutation was detected in one PCMS family without breast cancer. None of the reported germline mutations in the NOD2, Palladin, ARL11 or CHEK2 genes were detected in either type of family. In conclusion, families with an accumulation of PC and melanoma show a large variety of phenotypic expression, which is not always consistent with the FAMMM-PC phenotype. More PC/melanoma-prone families need to be analysed to clarify whether such families represent variations of the FAMMM-PC syndrome or two distinct hereditary cancer syndromes.