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Pancreatic Neoplasms: HELP
Articles by Christian Pilarsky
Based on 48 articles published since 2010
(Why 48 articles?)
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Between 2010 and 2020, C. Pilarsky wrote the following 48 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review CRISPR Cas9 in Pancreatic Cancer Research. 2019

Yang, Hai / Bailey, Peter / Pilarsky, Christian. ·Department for Surgical Research, Universitätsklinikum Erlangen, Erlangen, Germany. ·Front Cell Dev Biol · Pubmed #31681770.

ABSTRACT: Pancreatic cancer is now becoming a common cause of cancer death with no significant change in patient survival over the last 10 years. The main treatment options for pancreatic cancer patients are surgery, radiation therapy and chemotherapy, but there is now considerable effort to develop new and effective treatments. In recent years, CRISPR/Cas9 technology has emerged as a powerful gene editing tool with promise, not only as an important research methodology, but also as a new and effective method for targeted therapy. In this review, we summarize current advances in CRISPR/Cas9 technology and its application to pancreatic cancer research, and importantly as a means of selectively targeting key drivers of pancreatic cancer.

2 Review Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions. 2019

Brunner, Maximilian / Wu, Zhiyuan / Krautz, Christian / Pilarsky, Christian / Grützmann, Robert / Weber, Georg F. ·Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany. Maximilian.Brunner@uk-erlangen.de. · Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany. zhiyuan.wu@fau.de. · Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany. Christian.Krautz@uk-erlangen.de. · Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany. Christian.Pilarsky@uk-erlangen.de. · Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany. Robert.Gruetzmann@uk-erlangen.de. · Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany. Georg.weber@uk-erlangen.de. ·Int J Mol Sci · Pubmed #31540286.

ABSTRACT: Pancreatic cancer is one of the most lethal malignancies and is associated with a poor prognosis. Surgery is considered the only potential curative treatment for pancreatic cancer, followed by adjuvant chemotherapy, but surgery is reserved for the minority of patients with non-metastatic resectable tumors. In the future, neoadjuvant treatment strategies based on molecular testing of tumor biopsies may increase the amount of patients becoming eligible for surgery. In the context of non-metastatic disease, patients with resectable or borderline resectable pancreatic carcinoma might benefit from neoadjuvant chemo- or chemoradiotherapy followed by surgeryPatients with locally advanced or (oligo-/poly-)metastatic tumors presenting significant response to (neoadjuvant) chemotherapy should undergo surgery if R0 resection seems to be achievable. New immunotherapeutic strategies to induce potent immune response to the tumors and investigation in molecular mechanisms driving tumorigenesis of pancreatic cancer may provide novel therapeutic opportunities in patients with pancreatic carcinoma and help patient selection for optimal treatment.

3 Review Chemoresistance in Pancreatic Cancer. 2019

Zeng, Siyuan / Pöttler, Marina / Lan, Bin / Grützmann, Robert / Pilarsky, Christian / Yang, Hai. ·Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. siyuan.zeng365@gmail.com. · Department of Otorhinolaryngology, Head and Neck Surgery, Universitätsklinikum Erlangen, Glückstraße 10a, 91054 Erlangen, Germany. Marina.Poettler@uk-erlangen.de. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. bin.lan1991@gmail.com. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. Robert.Gruetzmann@uk-erlangen.de. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. christian.pilarsky@uk-erlangen.de. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. Hai.Yang@uk-erlangen.de. ·Int J Mol Sci · Pubmed #31514451.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.

4 Review The Role of Exosomes in Pancreatic Cancer. 2019

Lan, Bin / Zeng, Siyuan / Grützmann, Robert / Pilarsky, Christian. ·Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. bin.lan1991@gmail.com. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. siyuan.zeng365@gmail.com. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. Robert.Gruetzmann@uk-erlangen.de. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. christian.pilarsky@uk-erlangen.de. ·Int J Mol Sci · Pubmed #31487880.

ABSTRACT: Pancreatic cancer remains one of the deadliest cancers in the world, as a consequence of late diagnosis, early metastasis and limited response to chemotherapy, under which conditions the potential mechanism of pancreatic cancer progression requires further study. Exosomes are membrane vesicles which are important in the progression, metastasis and chemoresistance in pancreatic cancer. Additionally, they have been verified to be potential as biomarkers, targets and drug carriers for pancreatic cancer treatment. Thus, studying the role of exosomes in pancreatic cancer is significant. This paper focuses on the role of exosomes in the proliferation, metastasis and chemoresistance, as well as their potential applications for pancreatic cancer.

5 Review Genomics of pancreatic ductal adenocarcinoma. 2014

Pilarsky, Christian / Grutzmann, Robert. ·Department of Vascular-, Thoracic and Visceral Surgery, University Hospital Dresden, Technische Universit?t Dresden, Fetscherstr. 74, Dresden 01307, Germany. christian.pilarsky@gmail.com. ·Hepatobiliary Pancreat Dis Int · Pubmed #25100122.

ABSTRACT: Pancreatic cancer is one of the worst prognostic cancers because of the late diagnosis and the absence of effective treatment. Within all subtypes of this disease, ductal adenocarcinoma has the shortest survival time. In recent years, global genomics profiling allowed the identification of hundreds of genes that are perturbed in pancreatic cancer. The integration of different omics sources in the study of pancreatic cancer has revealed several molecular mechanisms, indicating the complex history of its development. However, validation of these genes as biomarkers for early diagnosis, prognosis or treatment efficacy is still incomplete but should lead to new approaches for the treatment of the disease in the future.

6 Review Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. 2014

Distler, M / Aust, D / Weitz, J / Pilarsky, C / Grützmann, Robert. ·Department of Visceral, Thoracic, and Vascular Surgery, University Hospital Carl Gustav Carus Dresden, TU Dresden, Fetscher Street 74, 01307 Dresden, Germany. · Institute for Pathology, University Hospital Carl Gustav Carus Dresden, TU Dresden, Fetscher Street 74, 01307 Dresden, Germany. ·Biomed Res Int · Pubmed #24783207.

ABSTRACT: Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures.

7 Review DNA methylation in pancreatic cancer: protocols for the isolation of DNA and bisulfite modification. 2012

Biewusch, Katja / Heyne, Marie / Grützmann, Robert / Pilarsky, Christian. ·Department of Surgery, University Hospital Dresden, Fetscherstraße, Dresden, Germany. ·Methods Mol Biol · Pubmed #22359299.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and still remains a challenge for its lack of effective therapeutic strategies, which is due to the late diagnosis of this disease. Methylation markers might improve early detection and surveillance of PDAC. Furthermore, analysis of hypermethylation in the tumor tissue might help to identify new targets for therapeutic intervention and improve the understanding of the pathophysiological changes occurring in pancreatic cancer. Methylation specific PCR is the method of choice if a small number of genes will be tested in a larger set of patient samples. After DNA isolation by standard procedure, the DNA is then modified using sodium bisulfite. This DNA can then be used in qualitative and quantitative PCR assays.

8 Review An update on molecular research of pancreatic adenocarcinoma. 2011

Krautz, Christian / Rückert, Felix / Saeger, Hans-Detlev / Pilarsky, Christian / Grützmann, Robert. ·Department of General, Thoracic, and Vascular Surgery, University Hospital Carl-Gustav-Carus Dresden, Germany. christian.krautz@uniklinikum-dresden.de ·Anticancer Agents Med Chem · Pubmed #21492076.

ABSTRACT: INTRODUCTION: This review provides an overview of the molecular mechanisms and pathways known to enhance development and progression of pancreatic ductal adenocarcinoma (PDAC). RESULTS: Today, the concept that progression of epithelial precursor lesions leads to invasive PDAC as a result of accumulating mutation in K-ras, p16(INK4A), p53 and Smad4 is widely accepted. Multiple signaling pathways that PDAC utilizes to acquire its tumorigenic features have been identified. Recent data suggest that reactivated developmental signaling pathways play a role in oncogenesis of PDAC. Furthermore, it is now clear that the tumor microenvironment actively promotes invasion and tumor growth through a complex of interactions of different cellular components. CONCLUSION: PDAC is still a challenging entity for physicians and scientists. Despite of recent advances in understanding its molecular biology, treatment options remain limited. Distinct tumor stroma interactions and apoptotic resistance lead to frequent failure of current chemotherapy. An early and aggressive tumor infiltration in combination with a late diagnosis prevents successful surgical therapy. Thus, our primary goal remains to translate the increasing knowledge of molecular pathogenesis of this disease into successful therapeutic strategies. Apart from tumor cell biology, the complex interactions of PDAC cells with their microenvironment have to be focus of future molecular research.

9 Review Recent patents concerning targeted therapy of apoptosis resistance in pancreatic cancer. 2011

Werner, Kristin / Rückert, Felix / Saeger, Hans-Detlev / Grützmann, Robert / Pilarsky, Christian. ·Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany. kristin.werner@uniklinikum-dresden.de ·Recent Pat DNA Gene Seq · Pubmed #21194411.

ABSTRACT: Pancreatic cancer is one of the most malignant forms of cancer. Due to numerous defects of the apoptosis machinery this tumor shows a high resistance towards conventional oncological therapies. On the level of the extrinsic pathway, signal transduction is flawed by over-expression of decoy receptors but also by a dysfunctional death inducing signaling complex (DISC). The mitochondrial pathway, normally stimulated by cell stress and toxic agents is impeded by over-expression of anti-apoptotic members of the Bcl 2 protein family and the so-called inhibitor of apoptosis proteins (IAPs). To overcome the dysfunction of the apoptosis pathway, new therapeutics focus on molecular targets within the apoptosis pathway. Recently, many new treatment modalities have been reported like recombinant ligands of the cell death receptors or inhibitors of anti-apoptotic Bcl-2 members. Furthermore, various substances for the direct activation of the caspase cascade were patented and the over-expression of IAPs could be treated by binding inhibitors or using RNA interference techniques. The present review aims at giving an overview on these new treatment modalities.

10 Review Intraductal papillary mucinous tumors of the pancreas: biology, diagnosis, and treatment. 2010

Grützmann, Robert / Niedergethmann, Marco / Pilarsky, Christian / Klöppel, Günter / Saeger, Hans D. ·University Hospital Carl Gustav Carus, Department of General, Vascular, and Thoracic Surgery, Dresden, Germany. Robert.Gruetzmann@uniklinikum-dresden.de ·Oncologist · Pubmed #21147870.

ABSTRACT: Pancreatic intraductal papillary mucinous neoplasms (IPMNs) rank among the most common cystic tumors of the pancreas. For a long time they were misdiagnosed as mucinous cystadenocarcinoma, ductal adenocarcinoma in situ, or chronic pancreatitis. Only in recent years have IPMNs been fully recognized as clinical and pathological entities, although their origin and molecular pathogenesis remain poorly understood. IPMNs are precursors of invasive carcinomas. When resected in a preinvasive state patient prognosis is excellent, and even when they are already invasive, patient prognosis is more favorable than with ductal adenocarcinomas. Subdivision into macroscopic and microscopic subtypes facilitates further patient risk stratification and directly impacts treatment. There are main duct and branch duct IPMNs, with the main duct type including the intestinal, pancreatobiliary, and oncocytic types and the branch duct type solely harboring the gastric type. Whereas main duct IPMNs have a high risk for malignant progression, demanding their resection, branch duct IPMNs have a much lower risk for harboring malignancy. Patients with small branch duct/gastric-type IPMNs (<2 cm) without symptoms or mural nodules can be managed by periodic surveillance.

11 Article Silenced ZNF154 Is Associated with Longer Survival in Resectable Pancreatic Cancer. 2019

Wiesmueller, Felix / Kopke, Josephin / Aust, Daniela / Roy, Janine / Dahl, Andreas / Pilarsky, Christian / Grützmann, Robert. ·Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), 91054 Erlangen, Germany. Felix.Wiesmueller@uk-erlangen.de. · Department of Urology, Asklepios Hospital Weißenfels, 06667 Weißenfels, Germany. Josephin.Kopke@gmx.de. · Institute of Pathology, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany. daniela.aust@uniklinikum-dresden.de. · Staburo GmbH, 81549 Munich, Germany. Janine.Roy@mail.de. · Dresden-Concept Genome Center, Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, 01307 Dresden, Germany. andreas.dahl@tu-dresden.de. · Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), 91054 Erlangen, Germany. christian.pilarsky@uk-erlangen.de. · Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), 91054 Erlangen, Germany. robert.gruetzmann@uk-erlangen.de. ·Int J Mol Sci · Pubmed #31683647.

ABSTRACT: Pancreatic cancer has become the third leading cause of cancer-related death in the Western world despite advances in therapy of other cancerous lesions. Late diagnosis due to a lack of symptoms during early disease allows metastatic spread of the tumor. Most patients are considered incurable because of metastasized disease. On a cellular level, pancreatic cancer proves to be rather resistant to chemotherapy. Hence, early detection and new therapeutic targets might improve outcomes. The detection of DNA promoter hypermethylation has been described as a method to identify putative genes of interest in cancer entities. These genes might serve as either biomarkers or might lead to a better understanding of the molecular mechanisms involved. We checked tumor specimens from 80 patients who had undergone pancreatic resection for promoter hypermethylation of the zinc finger protein ZNF154. Then, we further characterized the effects of ZNF154 on cell viability and gene expression by in vitro experiments. We found a significant association between ZNF154 hypermethylation and better survival in patients with resectable pancreatic cancer. Moreover, we suspect that the cell growth suppressor SLFN5 might be linked to a silenced ZNF154 in pancreatic cancer.

12 Article c-Met and PD-L1 on Circulating Exosomes as Diagnostic and Prognostic Markers for Pancreatic Cancer. 2019

Lux, Alexander / Kahlert, Christoph / Grützmann, Robert / Pilarsky, Christian. ·Medizinische Klinik III, Universitätsklinikum Carl Gustav Carus Dresden, Fetscherstraße 74, 01307 Dresden, Germany. · Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Carl Gustav Carus Dresden, Fetscherstraße 74, 01307 Dresden, Germany. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. christian.pilarsky@uk-erlangen.de. ·Int J Mol Sci · Pubmed #31284422.

ABSTRACT: Exosomes are membrane vesicles which offer potential as blood derived biomarkers for malign tumors in clinical practice. Pancreatic cancer is counted among cancer diseases with the highest mortality. The present work seeks to assess whether pancreatic carcinomas release exosomes which express c-Met (proto-oncogene mesenchymal-epithelial transition factor) and PD-L1 (programmed cell death 1 ligand 1), and whether the detection of such expression in serum has diagnostic or prognostic meaning for the affected patients. Exosome isolation was performed on culture media of one benign pancreatic cell line and ten pancreatic carcinoma cell lines as well as on serum samples from 55 patients with pancreatic ductal adenocarcinoma (PDAC), 26 patients with chronic pancreatitis and 10 patients with benign serous cyst adenoma of the pancreas. Exosomes were bound to latex beads and stained with antibodies against c-Met or PD-L1. Analysis of fluorescence intensity was performed by flow cytometry. In terms of c-Met, the mean fluorescence intensity of PDAC-patients was significantly higher than the fluorescence intensity of the comparative patients with benign disease (

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

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

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

14 Article Development of a Class Prediction Model to Discriminate Pancreatic Ductal Adenocarcinoma from Pancreatic Neuroendocrine Tumor by MALDI Mass Spectrometry Imaging. 2019

Casadonte, Rita / Kriegsmann, Mark / Perren, Aurel / Baretton, Gustavo / Deininger, Sören-Oliver / Kriegsmann, Katharina / Welsch, Thilo / Pilarsky, Christian / Kriegsmann, Jörg. ·Proteopath GmbH, Trier, 54296, Germany. · Institute of Pathology, University of Heidelberg, Heidelberg, 69120, Germany. · Institute of Pathology, University of Bern, Bern, 3012, Switzerland. · Institute of Pathology, University Hospital Carl Gustav Carus at the Technical University of Dresden, Dresden, 01307, Germany. · Bruker Daltonik, Bremen, 28359, Germany. · Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, 69120, Germany. · MVZ for Histology, Cytology and Molecular Diagnostics, Trier, 54296, Germany. ·Proteomics Clin Appl · Pubmed #30548962.

ABSTRACT: PURPOSE: To define proteomic differences between pancreatic ductal adenocarcinoma (pDAC) and pancreatic neuroendocrine tumor (pNET) by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). EXPERIMENTAL DESIGN: Ninety-three pDAC and 126 pNET individual tissues are assembled in tissue microarrays and analyzed by MALDI MSI. The cohort is separated in a training (52 pDAC and 83 pNET) and validation set (41 pDAC and 43 pNET). Subsequently, a linear discriminant analysis (LDA) model based on 46 peptide ions is performed on the training set and evaluated on the validation cohort. Additionally, two liver metastases and a whole slide of pDAC are analyzed by the same LDA algorithm. RESULTS: Classification of pDAC and pNET by the LDA model is correct in 95% (39/41) and 100% (43/43) of patients in the validation cohort, respectively. The two liver metastases and the whole slide of pDAC are also correctly classified in agreement with the histopathological diagnosis. CONCLUSION AND CLINICAL RELEVANCE: In the present study, a large dataset of pDAC and pNET by MALDI MSI is investigated, a class prediction model that allowed separation of both entities with high accuracy is developed, and differential peptide peaks with potential diagnostic, prognostic, and predictive values are highlighted.

15 Article Analysis of DNA Hypermethylation in Pancreatic Cancer Using Methylation-Specific PCR and Bisulfite Sequencing. 2018

Liu, Bin / Pilarsky, Christian. ·Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen, Erlangen, Germany. · Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen, Erlangen, Germany. christian.pilarsky@uk-erlangen.de. ·Methods Mol Biol · Pubmed #30178258.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor and the fourth common cause of cancer death in the Western world. The lack of effective therapeutic strategies is attributed to the late diagnosis of this disease. Methylation markers could improve early detection and help in the surveillance of PDAC after treatment. Analysis of hypermethylation in the tumor tissue and tumor-derived exosomes might help to identify new therapeutic strategies and aid in the understanding of the pathophysiological changes occurring in pancreatic cancer. There are several methods for the detection of methylation events. Whereas methylation-specific PCR (MSP-PCR) is the method of choice, the cost reductions in DNA sequencing enables researchers to add bisulfite sequencing (BSS) to their repertoire if a small number of genes will be tested in a larger set of patients' samples. During the last years, several techniques to isolate and analyze DNA methylation have been proposed, but DNA modification using sodium bisulfite is still the gold standard.

16 Article The Effect of GPRC5a on the Proliferation, Migration Ability, Chemotherapy Resistance, and Phosphorylation of GSK-3β in Pancreatic Cancer. 2018

Liu, Bin / Yang, Hai / Pilarsky, Christian / Weber, Georg F. ·Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. Liu.Bin@uk-erlangen.de. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. Hai.Yang@uk-erlangen.de. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. christian.pilarsky@uk-erlangen.de. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, 91054 Erlangen, Germany. Georg.Weber@uk-erlangen.de. ·Int J Mol Sci · Pubmed #29949874.

ABSTRACT: Pancreatic cancer (PaCa) is the fourth leading cause of cancer-related death, and personalized targeted cancer therapy is becoming a promising treatment strategy for PaCa. The central approach of targeted therapy is to find a targetable key and an effective targeting method. In this study, the importance of

17 Article Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. 2018

Mayerle, Julia / Kalthoff, Holger / Reszka, Regina / Kamlage, Beate / Peter, Erik / Schniewind, Bodo / González Maldonado, Sandra / Pilarsky, Christian / Heidecke, Claus-Dieter / Schatz, Philipp / Distler, Marius / Scheiber, Jonas A / Mahajan, Ujjwal M / Weiss, F Ulrich / Grützmann, Robert / Lerch, Markus M. ·Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, München, Germany. · Section for Molecular Oncology, Institut for Experimental Cancer Research (IET), UKSH, Kiel, Germany. · Metanomics Health GmbH, Berlin, Germany. · metanomics GmbH, Berlin, Germany. · Department of Surgery, University Hospital, Erlangen, Germany. · Department of General, Visceral, Thoracic and Vascular Surgery University Medicine Greifswald, Ernst-Moritz-Arndt University, Greifswald, Germany. · Clinic and Outpatient Clinic for Visceral-, Thorax- and Vascular Surgery, Medizinische Fakultät, TU Dresden, Dresden, Germany. ·Gut · Pubmed #28108468.

ABSTRACT: OBJECTIVE: Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose. DESIGN: For a case-control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. RESULTS: A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93-0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%-97.0%). In the test set, an AUC of 0.94 (95% CI 0.91-0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%-95.5%) and a specificity of 91.3% (95% CI 82.8%-96.4%) were achieved, successfully validating the biomarker signature. CONCLUSIONS: In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%-99.9%) (training set) and 99.8% (95% CI 99.6%-99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9.

18 Article Detection of COPB2 as a KRAS synthetic lethal partner through integration of functional genomics screens. 2017

Christodoulou, Eleni G / Yang, Hai / Lademann, Franziska / Pilarsky, Christian / Beyer, Andreas / Schroeder, Michael. ·Biotechnology Center, TU Dresden, Germany. · Department of Medical Oncology, National Cancer Center of Singapore, Singapore. · Chirurgische Klinik, Translational Research Center, Universitätsklinikum Erlangen, Germany. · Medizinische Fakultät Carl Gustav Carus, TU Dresden, Germany. · Cellular Networks and Systems Biology, University of Cologne, Germany. ·Oncotarget · Pubmed #28415695.

ABSTRACT: Mutated KRAS plays an important role in many cancers. Although targeting KRAS directly is difficult, indirect inactivation via synthetic lethal partners (SLPs) is promising. Yet to date, there are no SLPs from high-throughput RNAi screening, which are supported by multiple screens. Here, we address this problem by aggregating and ranking data over three independent high-throughput screens. We integrate rankings by minimizing the displacement and by considering established methods such as RIGER and RSA.Our meta analysis reveals COPB2 as a potential SLP of KRAS with good support from all three screens. COPB2 is a coatomer subunit and its knock down has already been linked to disabled autophagy and reduced tumor growth. We confirm COPB2 as SLP in knock down experiments on pancreas and colorectal cancer cell lines.Overall, consistent integration of high throughput data can generate candidate synthetic lethal partners, which individual screens do not uncover. Concretely, we reveal and confirm that COPB2 is a synthetic lethal partner of KRAS and hence a promising cancer target. Ligands inhibiting COPB2 may, therefore, be promising new cancer drugs.

19 Article The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. 2017

Krebs, Angela M / Mitschke, Julia / Lasierra Losada, María / Schmalhofer, Otto / Boerries, Melanie / Busch, Hauke / Boettcher, Martin / Mougiakakos, Dimitrios / Reichardt, Wilfried / Bronsert, Peter / Brunton, Valerie G / Pilarsky, Christian / Winkler, Thomas H / Brabletz, Simone / Stemmler, Marc P / Brabletz, Thomas. ·Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany. · University of Freiburg, Faculty of Biology, Schaenzlestrasse 1, 79104 Freiburg, Germany. · German Cancer Consortium (DKTK), 79106 Freiburg, Germany. · German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany. · Department of General and Visceral Surgery, University of Freiburg Medical Center, Hugstetter Strasse 55, 79106 Freiburg, Germany. · Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research (IMMZ), Albert-Ludwigs-University Freiburg, Stefan-Meier-Strasse 17, 79106 Freiburg, Germany. · Department of Internal Medicine 5, Hematology and Oncology, Universitätsklinikum, FAU University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany. · Department of Radiology Medical Physics, University Medical Center, Freiburg, Breisacher Strasse 60a, 79106 Freiburg, Germany. · Institute of Pathology and Comprehensive Cancer Center, University Medical Center, Freiburg, Breisacher Strasse 115a, 79106 Freiburg, Germany. · Edinburgh Cancer Research Centre, Institute of Genetics &Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK. · Department of Surgery, Universitätsklinikum, FAU University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany. · Chair of Genetics, Nikolaus-Fiebiger-Center for Molecular Medicine, Department Biology, FAU University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany. ·Nat Cell Biol · Pubmed #28414315.

ABSTRACT: Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously.

20 Article The G Protein-Coupled Receptor RAI3 Is an Independent Prognostic Factor for Pancreatic Cancer Survival and Regulates Proliferation via STAT3 Phosphorylation. 2017

Jahny, Elisabeth / Yang, Hai / Liu, Bin / Jahnke, Beatrix / Lademann, Franziska / Knösel, Thomas / Rümmele, Petra / Grützmann, Robert / Aust, Daniela E / Pilarsky, Christian / Denz, Axel. ·Department of Surgery, TU Dresden, Fetscherstraße 74, Dresden, Germany. · Department of Surgery, Universitätsklinikum Erlangen, Krankenhausstraße 12, Erlangen, Germany. · Institute of Pathology, Ludwig-Maximilians-Universität München, München, Germany. · Institute of Pathology, Universitätsklinikum Erlangen, Krankenhausstraße 8-10, Erlangen, Germany. · Institute of Pathology, TU Dresden, Fetscherstraße 74, Dresden, Germany. ·PLoS One · Pubmed #28114355.

ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest tumors worldwide. Understanding the function of gene expression alterations is a prerequisite for developing new strategies in diagnostic and therapy. GPRC5A (RAI3), coding for a seven transmembrane G protein-coupled receptor is known to be overexpressed in pancreatic cancer and might be an interesting candidate for therapeutic intervention. Expression levels of RAI3 were compared using a tissue microarray of 435 resected patients with pancreatic cancer as well as 209 samples from chronic pancreatitis (CP), intra-ductal papillary mucinous neoplasm (IPMN) and normal pancreatic tissue. To elucidate the function of RAI3 overexpression, siRNA based knock-down was used and transfected cells were analyzed using proliferation and migration assays. Pancreatic cancer patients showed a statistically significant overexpression of RAI3 in comparison to normal and chronic pancreatitis tissue. Especially the loss of apical RAI3 expression represents an independent prognostic parameter for overall survival of patients with pancreatic cancer. Suppression of GPRC5a results in decreased cell growth, proliferation and migration in pancreatic cancer cell lines via a STAT3 modulated pathway, independent from ERK activation.

21 Article Hypermutation In Pancreatic Cancer. 2017

Humphris, Jeremy L / Patch, Ann-Marie / Nones, Katia / Bailey, Peter J / Johns, Amber L / McKay, Skye / Chang, David K / Miller, David K / Pajic, Marina / Kassahn, Karin S / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Stone, Andrew / Wilson, Peter J / Anderson, Matthew / Fink, J Lynn / Holmes, Oliver / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Mead, Ronald S / Xu, Qinying / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Nagrial, Adnan M / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Chou, Angela / Scarlett, Christopher J / Pinho, Andreia V / Rooman, Ilse / Giry-Laterriere, Marc / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Jamieson, Nigel B / McKay, Colin J / Carter, C Ross / Dickson, Euan J / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Morton, Jennifer P / Sansom, Owen J / Grützmann, Robert / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Rusev, Borislav / Corbo, Vincenzo / Salvia, Roberto / Cataldo, Ivana / Tortora, Giampaolo / Tempero, Margaret A / Anonymous5070887 / Hofmann, Oliver / Eshleman, James R / Pilarsky, Christian / Scarpa, Aldo / Musgrove, Elizabeth A / Gill, Anthony J / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. · Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. · Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia. · School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. · Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. · Universitätsklinikum Erlangen, Erlangen, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. · Division of Hematology and Oncology, University of California, San Francisco, California. · Australian Pancreatic Cancer Genome Initiative. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Universitätsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #27856273.

ABSTRACT: Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

22 Article In silico analysis of the transportome in human pancreatic ductal adenocarcinoma. 2016

Zaccagnino, A / Pilarsky, C / Tawfik, D / Sebens, S / Trauzold, A / Novak, I / Schwab, A / Kalthoff, H. ·Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, UKSH, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany. angela.zacca@email.uni-kiel.de. · Department of Surgery, University Clinic, Krankenhausstr. 12, 91054, Erlangen, Germany. · Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, UKSH, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany. · Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark. · Institute of Physiology II, University of Muenster, Robert-Koch-Str. 27 b, 48149, Muenster, Germany. · Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, UKSH, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Germany. holger.kalthoff@email.uni-kiel.de. ·Eur Biophys J · Pubmed #27652669.

ABSTRACT: The altered expression and/or activity of ion channels and transporters (transportome) have been associated with malignant behavior of cancer cells and were proposed to be a hallmark of cancer. However, the impact of altered transportome in epithelial cancers, such as pancreatic ductal adenocarcinoma (PDAC), as well as its pathophysiological consequences, still remains unclear. Here, we report the in silico analysis of 840 transportome genes in PDAC patients' tissues. Our study was focused on the transportome changes and their correlation with functional and behavioral responses in PDAC tumor and stromal compartments. The dysregulated gene expression datasets were filtered using a cut-off of fold-change values ≤-2 or ≥2 (adjusted p value ≤0.05). The dysregulated transportome genes were clearly associated with impaired physiological secretory mechanisms and/or pH regulation, control of cell volume, and cell polarity. Additionally, some down-regulated transportome genes were found to be closely linked to epithelial cell differentiation. Furthermore, the observed decrease in genes coding for calcium and chloride transport might be a mechanism for evasion of apoptosis. In conclusion, the current work provides a comprehensive overview of the altered transportome expression and its association with predicted PDAC malignancy with special focus on the epithelial compartment.

23 Article Genomic analyses identify molecular subtypes of pancreatic cancer. 2016

Bailey, Peter / Chang, David K / Nones, Katia / Johns, Amber L / Patch, Ann-Marie / Gingras, Marie-Claude / Miller, David K / Christ, Angelika N / Bruxner, Tim J C / Quinn, Michael C / Nourse, Craig / Murtaugh, L Charles / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourbakhsh, Ehsan / Wani, Shivangi / Fink, Lynn / Holmes, Oliver / Chin, Venessa / Anderson, Matthew J / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Xu, Qinying / Wilson, Peter J / Cloonan, Nicole / Kassahn, Karin S / Taylor, Darrin / Quek, Kelly / Robertson, Alan / Pantano, Lorena / Mincarelli, Laura / Sanchez, Luis N / Evers, Lisa / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chantrill, Lorraine A / Mawson, Amanda / Humphris, Jeremy / Chou, Angela / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia V / Giry-Laterriere, Marc / Rooman, Ilse / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Moran-Jones, Kim / Jamieson, Nigel B / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Grützmann, Robert / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Corbo, Vincenzo / Bassi, Claudio / Rusev, Borislav / Capelli, Paola / Salvia, Roberto / Tortora, Giampaolo / Mukhopadhyay, Debabrata / Petersen, Gloria M / Anonymous2640859 / Munzy, Donna M / Fisher, William E / Karim, Saadia A / Eshleman, James R / Hruban, Ralph H / Pilarsky, Christian / Morton, Jennifer P / Sansom, Owen J / Scarpa, Aldo / Musgrove, Elizabeth A / Bailey, Ulla-Maja Hagbo / Hofmann, Oliver / Sutherland, Robert L / Wheeler, David A / Gill, Anthony J / Gibbs, Richard A / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. · The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. · Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. · Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. · School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. · Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. · Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. · Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. · St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney, Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. · School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. · Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. · Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. · Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. · Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. · The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. · Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. · University of Melbourne, Parkville, Victoria 3010, Australia. ·Nature · Pubmed #26909576.

ABSTRACT: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

24 Article Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation. 2016

Gingras, Marie-Claude / Covington, Kyle R / Chang, David K / Donehower, Lawrence A / Gill, Anthony J / Ittmann, Michael M / Creighton, Chad J / Johns, Amber L / Shinbrot, Eve / Dewal, Ninad / Fisher, William E / Anonymous400856 / Pilarsky, Christian / Grützmann, Robert / Overman, Michael J / Jamieson, Nigel B / Van Buren, George / Drummond, Jennifer / Walker, Kimberly / Hampton, Oliver A / Xi, Liu / Muzny, Donna M / Doddapaneni, Harsha / Lee, Sandra L / Bellair, Michelle / Hu, Jianhong / Han, Yi / Dinh, Huyen H / Dahdouli, Mike / Samra, Jaswinder S / Bailey, Peter / Waddell, Nicola / Pearson, John V / Harliwong, Ivon / Wang, Huamin / Aust, Daniela / Oien, Karin A / Hruban, Ralph H / Hodges, Sally E / McElhany, Amy / Saengboonmee, Charupong / Duthie, Fraser R / Grimmond, Sean M / Biankin, Andrew V / Wheeler, David A / Gibbs, Richard A. ·Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: mgingras@bcm.edu. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, NSW 2170, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. · The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia; Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Michael E. DeBakey Department of Veterans Affairs Medical Center, Houston, TX 77030, USA. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. · The Kinghorn Cancer Centre and the Cancer Research Program Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA. · Department of Surgery, TU Dresden, 01307 Dresden, Germany. · Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK; Academic Unit of Surgery, Institute of Cancer Sciences, Glasgow Royal Infirmary, Level 2, New Lister Building, University of Glasgow, Glasgow G31 2ER, UK. · Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. · Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, TU Dresden, 01307 Dresden, Germany. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Department of Pathology, Southern General Hospital, Greater Glasgow and Clyde NHS, Glasgow G51 4TF, UK. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA; The Elkins Pancreas Center at Baylor College of Medicine, Houston, TX 77030, USA. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand. · Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Bearsden, Glasgow G61 1BD, UK; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wheeler@bcm.edu. ·Cell Rep · Pubmed #26804919.

ABSTRACT: The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

25 Article Simultaneous gene silencing of KRAS and anti-apoptotic genes as a multitarget therapy. 2016

Werner, Kristin / Lademann, Franziska / Thepkaysone, May-Linn / Jahnke, Beatrix / Aust, Daniela E / Kahlert, Christoph / Weber, Georg / Weitz, Jürgen / Grützmann, Robert / Pilarsky, Christian. ·Department of Visceral, Thoracic and Vascular Surgery, TU Dresden, 01307 Dresden, Germany. · Institute of Pathology, TU Dresden, 01307 Dresden, Germany. · Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany. ·Oncotarget · Pubmed #26716649.

ABSTRACT: Pancreatic cancer is one of the most lethal tumor types worldwide and an effective therapy is still elusive. Targeted therapy focused against a specific alteration is by definition unable to attack broad pathway signaling modification. Tumor heterogeneity will render targeted therapies ineffective based on the regrowth of cancer cell sub-clones. Therefore multimodal therapy strategies, targeting signaling pathways simultaneously should improve treatment.SiRNAs against KRAS and the apoptosis associated genes BCLXL, FLIP, MCL1L, SURVIVIN and XIAP were transfected into human and murine pancreatic cancer cell lines. Induction of apoptosis was measured by Caspase 3/7 activation, subG1 FACS analysis and PARP cleavage. The therapeutic approach was tested in a subcutaneous allograft model with a murine cancer cell line.By using siRNAs as a systematic approach to remodel signal transduction in pancreatic cancer the results showed increasing inhibition of proliferation and apoptosis induction in vitro and in vivo. Thus, siRNAs are suitable to model multimodal therapy against signaling pathways in pancreatic cancer. Improvements in in vivo delivery of siRNAs against a multitude of targets might therefore be a potential therapeutic approach.

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