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Pancreatic Neoplasms: HELP
Articles by Bence Sipos
Based on 52 articles published since 2010
(Why 52 articles?)
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Between 2010 and 2020, B. Sipos wrote the following 52 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review [Classification and malignant potential of pancreatic cystic tumors]. 2015

Esposito, I / Schlitter, A M / Sipos, B / Klöppel, G. ·Institut für Pathologie und Pathologische Anatomie, Technische Universität München, Ismaningerstr. 22, 81675, München, Deutschland, esposito@lrz.tum.de. ·Pathologe · Pubmed #25663186.

ABSTRACT: Cystic lesions of the pancreas are increasingly diagnosed with a reported prevalence of 10 % in 70-year-old individuals. Despite their broad spectrum, most resected cystic lesions can be attributed to one of the following entities: intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), neuroendocrine cystic tumors (NECT), and solid pseudopapillary neoplasms (SPN). Among them, IPMN and MCN represent precursors of ductal adenocarcinoma, NECT and SPN are low-grade, potentially malignant lesions, and SCN are usually benign. Due to the not negligible morbidity and mortality rates in pancreatic surgery, even in highly specialized centers, an interdisciplinary preoperative stratification of pancreatic cystic lesions into high- and low-risk tumors is necessary in order to accurately select those cases that need to undergo immediate resection. The role of the pathologist is fundamental in both the preoperative assessment and in the postoperative classification, which determines prognosis, further treatment, and follow-up.

2 Review Hyperplasia to neoplasia sequence of duodenal and pancreatic neuroendocrine diseases and pseudohyperplasia of the PP-cells in the pancreas. 2014

Klöppel, Günter / Anlauf, Martin / Perren, Aurel / Sipos, Bence. ·Department of Pathology, Technical University, Ismaningerstr. 22, 81675, München, Germany, guenter.kloeppel@alumni.uni-kiel.de. ·Endocr Pathol · Pubmed #24718881.

ABSTRACT: Hyperplastic changes of the neuroendocrine cell system may have the potential to evolve into neoplastic diseases. This is particularly the case in the setting of genetically determined and hereditary neuroendocrine tumor syndromes such as MEN1. The review discusses the MEN1-associated hyperplasia-neoplasia sequence in the development of gastrinomas in the duodenum and glucagon-producing tumors in the pancreas. It also presents other newly described diseases (e.g., glucagon cell adenomatosis and insulinomatosis) in which the tumors are (or most likely) also preceded by islet cell hyperplasia. Finally, the pseudohyperplasia of PP-rich islets in the pancreatic head is defined as a physiologic condition clearly differing from other hyperplastic-neoplastic neuroendocrine diseases.

3 Review [Will molecular diagnostics become established in pancreatic pathology?]. 2013

Sipos, B / Sperveslage, J. ·Allgemeine Pathologie und Pathologische Anatomie, Institut für Pathologie und Neuropathologie, Universitätsklinikum Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Deutschland, bence.sipos@med.uni-tuebingen.de. ·Pathologe · Pubmed #24196616.

ABSTRACT: Genetic alterations of solid and cystic tumors of the pancreas have been increasingly more characterized over the last few years. Pancreatic ductal adenocarcinoma (PDAC) carries numerous point mutations and, to a lesser extent, deletions and amplifications of genes that are associated with at least 13 tumor relevant signalling pathways and processes. Besides the four common driver mutations in the KRAS, p53, CDKN2a and SMAD4 genes there are a number of low frequency driver mutations. The classification of PDAC subtypes has benefited from recent analyses of transcriptional profiles that revealed a classical KRAS driven and a KRAS independent quasi-mesenchymal subtype. The analyses of mRNA and miRNA expression profiles of fine needle aspirates serve as a basis for reliable preoperative diagnosis of pancreatic masses.The four most common cystic pancreatic tumors bear tumor-specific genetic alterations, such as GNAS mutations in intraductal papillary mucinous neoplasms, β-catenin mutations in solid pseudopapillary neoplasms and VHL mutations or loss of heterozygosity in serous cystadenoma. Recovery of DNA from aspirates of cyst fluids enables an improved preoperative management of cystic pancreatic tumors by mutational analysis. In addition to the analysis of DNA there are promising approaches in distinguishing benign and premalignant/malignant cystic tumors by evaluating miRNA profiles.In recent years much progress has been made in molecular genetic characterization and preoperative evaluation of pancreatic tumors. Hopefully these results will contribute to prognostic and therapeutic stratification of PDAC and to a reliable preoperative diagnostics of benign cystic pancreatic tumors in the future.

4 Review [Precursor lesions of pancreatobiliary cancer]. 2011

Sipos, B / Henopp, T. ·Abt. Allg. Pathologie und Pathologische Anatomie, Institut für Pathologie und Neuropathologie, Universitätsklinikum Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Deutschland. bence.sipos@med.uni-tuebingen.de ·Pathologe · Pubmed #21909795.

ABSTRACT: Precursor lesions of pancreatobiliary cancer can be divided into cystic and flat lesions. Mucinous cystic neoplasm and intraductal papillary mucinous neoplasm (IPMN) comprise the cystic precursors in the pancreas, while intraductal papillary neoplasm (IPN) represents their counterpart in the bile duct system. There is an adenoma-carcinoma sequence in the cystic precursors arising from four different types of epithelia: pancreatobiliary, oncocytic, intestinal and gastric. These subtypes of IPMN/IPN are morphologically and immunohistochemically well characterised and show clinical and prognostic relevance: the gastric subtype is associated with the best prognosis, followed by the oncocytic and intestinal subtypes, while the pancreatobiliary subtype is characterized by adverse clinical behaviour. Pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN) represent the flat precursors. PanIN are morphologically and biologically well defined. PanIN with lobulocentric atrophy has recently been described as a putative precursor of pancreatic cancer. Despite well defined morphological features in BilIN, the molecular alterations seen during early tumor progression in the biliary tract are poorly understood.

5 Clinical Trial pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104. 2014

Ormanns, Steffen / Siveke, Jens T / Heinemann, Volker / Haas, Michael / Sipos, Bence / Schlitter, Anna Melissa / Esposito, Irene / Jung, Andreas / Laubender, Rüdiger P / Kruger, Stephan / Vehling-Kaiser, Ursula / Winkelmann, Cornelia / Fischer von Weikersthal, Ludwig / Clemens, Michael R / Gauler, Thomas C / Märten, Angela / Geissler, Michael / Greten, Tim F / Kirchner, Thomas / Boeck, Stefan. ·Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, München, Germany. stefan.boeck@med.uni-muenchen.de. ·BMC Cancer · Pubmed #25164437.

ABSTRACT: BACKGROUND: The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined. METHODS: Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model. RESULTS: Fifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53. CONCLUSION: pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash. TRIAL REGISTRATION: NCT00440167 (registration date: February 22, 2007).

6 Clinical Trial Comparative characterization of stroma cells and ductal epithelium in chronic pancreatitis and pancreatic ductal adenocarcinoma. 2014

Helm, Ole / Mennrich, Ruben / Petrick, Domantas / Goebel, Lisa / Freitag-Wolf, Sandra / Röder, Christian / Kalthoff, Holger / Röcken, Christoph / Sipos, Bence / Kabelitz, Dieter / Schäfer, Heiner / Oberg, Hans-Heinrich / Wesch, Daniela / Sebens, Susanne. ·Institute for Experimental Medicine, Group Inflammatory Carcinogenesis, UKSH Campus Kiel, Kiel, Germany. · Institute of Immunology, UKSH Campus Kiel, Kiel, Germany. · Institute of Medical Informatics and Statistics, UKSH Campus Kiel, Kiel, Germany. · Institute of Experimental Cancer Research, UKSH Campus Kiel, Kiel, Germany. · Institute of Pathology, UKSH Campus Kiel, Kiel, Germany. · Institute of Pathology; University Tübingen, Tübingen, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH Campus Kiel, Kiel, Germany. ·PLoS One · Pubmed #24797069.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive stroma being also present in chronic pancreatitis (CP). Using immunohistochemistry, the stroma of CP and PDAC was comprehensively analyzed and correlated with epithelial/carcinoma-related alterations and clinicopathological patient characteristics. While there were no significant differences between CP and PDAC regarding the distribution of CD3+ T cells and α-SMA+ fibroblasts, proportions of CD4+ and CD8+ T cells were significantly lower and numbers of CD25+(CD4+) and FoxP3+(CD4+) regulatory T cells were greater in PDAC compared with CP. Macrophages were more prevalent in CP, but localized more closely to carcinoma cells in PDAC, as were γδ-T cells. Duct-related FoxP3 and L1CAM expression increased from CP to PDAC, while vimentin expression was similarly abundant in both diseases. Moreover, stromal and epithelial compartments of well-differentiated tumors and CPs shared considerable similarities, while moderately and poorly differentiated tumors significantly differed from CP tissues. Analysis of 27 parameters within each pancreatic disease revealed a significant correlation of i) CD4+ and FoxP3+CD4+ T cells with FoxP3 expression in PDAC cells, ii) α-SMA+ fibroblasts with L1CAM expression and proliferation in PDAC cells, iii) CD3 and CD8 expression with γδ-TCR expression in both pancreatic diseases and iv) CD68+ and CD163+ macrophages with vimentin expression in PDAC cells. High expression of FoxP3, vimentin and L1CAM in PDAC cells as well as a tumor-related localization of macrophages each tended to correlate with higher tumor grade. Multivariate survival analysis revealed a younger age at time of surgery as a positive prognostic marker for PDAC patients with the most frequently operated disease stage T3N1M0. Overall this study identified several interrelationships between stroma and epithelial/carcinoma cells in PDACs but also in CP, which in light of previous experimental data strongly support the view that the inflammatory stroma contributes to malignancy-associated alterations already in precursor cells during CP.

7 Article Inflammation Associated Pancreatic Tumorigenesis: Upregulation of Succinate Dehydrogenase (Subunit B) Reduces Cell Growth of Pancreatic Ductal Epithelial Cells. 2019

Rahn, Sascha / Barbosa, Philippe Dänzer / Möller, Julia Luisa / Ammar, Nourhane / Demetrowitsch, Tobias / Helm, Ole / Wesch, Daniela / Sipos, Bence / Röcken, Christoph / Schwarz, Karin / Schäfer, Heiner / Sebens, Susanne. ·Institute for Experimental Cancer Research, University of Kiel and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany. · Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany. · Institute for Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany. · Fraunhofer Institute for Toxicology and Experimental Medicine, 30625 Hannover, Germany. · Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany. · Institute for Human Nutrition & Food Science, Department of Food Technology, University of Kiel, 24118 Kiel, Germany. · Institute of Immunology, University of Kiel and UKSH Campus Kiel, 24105 Kiel, Germany. · BAG für Pathologie und Molekularpathologie Stuttgart, 70176 Stuttgart, Germany. · Department of Pathology, UKSH Campus Kiel, 24105 Kiel, Germany. ·Cancers (Basel) · Pubmed #31877753.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is amongst the most fatal malignancies and its development is highly associated with inflammatory processes such as chronic pancreatitis (CP). Since the succinate dehydrogenase subunit B (SDHB) is regarded as tumor suppressor that is lost during cancer development, this study investigated the impact of M1-macrophages as part of the inflammatory microenvironment on the expression as well as function of SDHB in benign and premalignant pancreatic ductal epithelial cells (PDECs). Immunohistochemical analyses on pancreatic tissue sections from CP patients and control individuals revealed a stronger SDHB expression in ducts of CP tissues being associated with a greater abundance of macrophages compared to ducts in control tissues. Accordingly, indirect co-culture with M1-macrophages led to clearly elevated SDHB expression and SDH activity in benign H6c7-pBp and premalignant H6c7-kras PDECs. While siRNA-mediated SDHB knockdown in these cells did not affect glucose and lactate uptake after co-culture, SDHB knockdown significantly promoted PDEC growth which was associated with increased proliferation and decreased effector caspase activity particularly in co-cultured PDECs. Overall, these data indicate that SDHB expression and SDH activity are increased in PDECs when exposed to pro-inflammatory macrophages as a counterregulatory mechanism to prevent excessive PDEC growth triggered by the inflammatory environment.

8 Article SPARC dependent collagen deposition and gemcitabine delivery in a genetically engineered mouse model of pancreas cancer. 2019

Ramu, Iswarya / Buchholz, Sören M / Patzak, Melanie S / Goetze, Robert G / Singh, Shiv K / Richards, Frances M / Jodrell, Duncan I / Sipos, Bence / Ströbel, Philipp / Ellenrieder, Volker / Hessmann, Elisabeth / Neesse, Albrecht. ·Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany. · Cancer Research UK Cambridge Institute, Li Ka Shing Centre, The University of Cambridge, United Kingdom. · Institute of Pathology and Neuropathology, University Clinic Tübingen, Germany. · Institute of Pathology, University Medical Centre Göttingen, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany. Electronic address: albrecht.neesse@med.uni-goettingen.de. ·EBioMedicine · Pubmed #31597597.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterised by extensive matrix deposition that has been implicated in impaired drug delivery and therapeutic resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates collagen deposition and is highly upregulated in the activated stroma subtype with poor prognosis in PDAC patients. METHODS: Kras FINDINGS: Global genetic ablation of SPARC in a Kras INTERPRETATION: Global SPARC ablation reduces the collagen-rich microenvironment in murine PDAC. Moreover, global SPARC depletion did not affect tumour growth kinetics, grading or metastatic frequency. Notably, the dense-collagen matrix did not restrict access of gemcitabine to the tumour. These findings may have direct translational implications in clinical trial design.

9 Article The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2. 2019

Kha, My-Lan / Hesse, Lisa / Deisinger, Florian / Sipos, Bence / Röcken, Christoph / Arlt, Alexander / Sebens, Susanne / Helm, Ole / Schäfer, Heiner. ·Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany. · Department of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Germany. · Institute of Pathology, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 14, Arnold-Heller-Straße 3, 24105, Kiel, Germany. · Biomaterial Bank of the Comprehensive Cancer Center Kiel, UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany. · Laboratory of Gastrointestinal Signal Transduction, Department of Internal Medicine I, UKSH Campus Kiel, Bldg. 6, Arnold-Heller-Straße 3, 24105 Kiel, Germany. · Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany. · Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany. hschaef@1med.uni-kiel.de. ·Oncogene · Pubmed #30302023.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While death rates show declining trends in the majority of cancers, PDAC registers rising rates. Based on the recently described crosstalk between TGF-β1 and Nrf2 in the PDAC development, the involvement of ATF3 and its splice variant ΔZip2 in TGF-β1- and Nrf2-driven pancreatic tumorigenesis was investigated. As demonstrated here, PDAC (Panc1, T3M4) cells or premalignant H6c7 pancreatic ductal epithelial cells differentially express ΔZip2- and ATF3, relating to stronger Nrf2 activity seen in Panc1 cells and TGF-ß1 activity in T3M4 or H6c7 cells, respectively. Treatment with the electrophile/oxidative stress inducer tBHQ or the cytostatic drug gemcitabine strongly elevated ΔZip2 expression in a Nrf2-dependent fashion. The differential expression of ATF3 and ΔZip2 in response to Nrf2 and TGF-ß1 relates to differential ATF3-gene promoter usage, giving rise of distinct splice variants. Nrf2-dependent ΔZip2 expression confers resistance against gemcitabine-induced apoptosis, only partially relating to interference with ATF3 and its proapoptotic activity, e.g., through CHOP-expression. In fact, ΔZip2 autonomously activates expression of cIAP anti-apoptotic proteins. Moreover, ΔZip2 favors and ATF3 suppresses growth and clonal expansion of PDAC cells, again partially independent of each other. Using a Panc1 tumor xenograft model in SCID-beige mice, the opposite activities of ATF3 and ΔZip2 on tumor-growth and chemoresistance were verified in vivo. Immunohistochemical analyses confirmed ΔZip2 and Nrf2 coexpression in cancerous and PanIN structures of human PDAC and chronic pancreatitis tissues, respectively, which to some extent was reciprocal to ATF3 expression. It is concluded that depending on selective ATF3-gene promoter usage by Nrf2, the ΔZip2 expression is induced in response to electrophile/oxidative (here through tBHQ) and xenobiotic (here through gemcitabine) stress, providing apoptosis protection and growth advantages to pancreatic ductal epithelial cells. This condition may substantially add to pancreatic carcinogenesis driven by chronic inflammation.

10 Article The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans. 2018

Gerst, Felicia / Jaghutriz, Benjamin A / Staiger, Harald / Schulte, Anke M / Lorza-Gil, Estela / Kaiser, Gabriele / Panse, Madhura / Haug, Sieglinde / Heni, Martin / Schütz, Monika / Stadion, Mandy / Schürmann, Annette / Marzetta, Flavia / Ibberson, Mark / Sipos, Bence / Fend, Falko / Fleming, Thomas / Nawroth, Peter P / Königsrainer, Alfred / Nadalin, Silvio / Wagner, Silvia / Peter, Andreas / Fritsche, Andreas / Richter, Daniela / Solimena, Michele / Häring, Hans-Ulrich / Ullrich, Susanne / Wagner, Robert. ·Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany. · German Center for Diabetes Research, Neuherberg, Germany. · Internal Medicine IV, University Hospital Tuebingen, Tübingen, Germany. · Department of Pharmacy and Biochemistry, Institute of Pharmaceutical Sciences, Eberhard Karls University of Tuebingen, Tübingen, Germany. · Diabetes Research, Sanofi-Aventis Deutschland GmbH, Frankfurt-am-Main, Germany. · Department of Medical Microbiology and Hygiene, Section of Cellular and Molecular Microbiology, University Hospital Tuebingen, Tübingen, Germany. · German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. · Vital-IT Group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. · Department of General Pathology and Pathological Anatomy, University Hospital Tuebingen, Tübingen, Germany. · Internal Medicine I, University Hospital Heidelberg, Heidelberg, Germany. · Department of General, Visceral and Transplant Surgery, University Hospital Tuebingen, Tübingen, Germany. · Institute for Pancreatic Islet Research, Dresden, Germany. ·J Clin Endocrinol Metab · Pubmed #30202879.

ABSTRACT: Context: Reduced β-cell mass, impaired islet function, and dedifferentiation are considered causal to development of hyperglycemia and type 2 diabetes. In human cohort studies, changes of islet cell-specific expression patterns have been associated with diabetes but not directly with in vivo insulin secretion. Objective: This study investigates alterations of islet gene expression and corresponding gene variants in the context of in vivo glycemic traits from the same patients. Methods: Fasting blood was collected before surgery, and pancreatic tissue was frozen after resection from 18 patients undergoing pancreatectomy. Islet tissue was isolated by laser capture microdissection. Islet transcriptome was analyzed using microarray and quantitative RT-PCR. Proteins were examined by immunohistochemistry and western blotting. The association of gene variants with insulin secretion was investigated with oral glucose tolerance test (OGTT)-derived insulin secretion measured in a large cohort of subjects at increased risk of type 2 diabetes and with hyperglycemic clamp in a subset. Results: Differential gene expression between islets from normoglycemic and hyperglycemic patients was prominent for the glycolytic enzyme ALDOB and the obesity-associated gene FAIM2. The mRNA levels of both genes correlated negatively with insulin secretion and positively with HbA1c. Islets of hyperglycemic patients displayed increased ALDOB immunoreactivity in insulin-positive cells, whereas α- and δ-cells were negative. Exposure of isolated islets to hyperglycemia augmented ALDOB expression. The minor allele of the ALDOB variant rs550915 associated with significantly higher levels of C-peptide and insulin during OGTT and hyperglycemic clamp, respectively. Conclusion: Our analyses suggest that increased ALDOB expression in human islets is associated with lower insulin secretion.

11 Article Therapeutic targeting of tumor-associated macrophages in pancreatic neuroendocrine tumors. 2018

Krug, Sebastian / Abbassi, Rami / Griesmann, Heidi / Sipos, Bence / Wiese, Dominik / Rexin, Peter / Blank, Annika / Perren, Aurel / Haybaeck, Johannes / Hüttelmaier, Stefan / Rinke, Anja / Gress, Thomas M / Michl, Patrick. ·Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. · Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany. · Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany. · Department of Visceral, Thoracic and Vascular Surgery, Philipps-University, Marburg, Germany. · Institute of Pathology, Philipps-University, Marburg, Germany. · Institute of Pathology, University of Bern, Bern, Switzerland. · Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany. · Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany. ·Int J Cancer · Pubmed #29696624.

ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behavior and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage, and grading. The effect of liposomal clodronate on TAM cell viability was analyzed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human, insulinomas TAM density was correlated with invasiveness and malignant behavior. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, Liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80-positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET and correlate with metastatic behavior. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis. Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET.

12 Article Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3. 2018

Konukiewitz, Björn / Jesinghaus, Moritz / Steiger, Katja / Schlitter, Anna Melissa / Kasajima, Atsuko / Sipos, Bence / Zamboni, Giuseppe / Weichert, Wilko / Pfarr, Nicole / Klöppel, Günter. ·Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: b.konukiewitz@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: moritz.jesinghaus@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: katja.steiger@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: melissa.schlitter@web.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: atsuko.kasajima@tum.de. · Institute of Pathology, University Hospital of Tuebingen, 72076 Tuebingen, Germany. Electronic address: Bence.Sipos@med.uni-tuebingen.de. · Institute of Pathology, Sacro Cuore Don Calabria Hospital, 37024 Negrar, Verona, Italy. Electronic address: giuseppe.zamboni@sacrocuore.it. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: wilko.weichert@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: nicole.pfarr@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: guenter.kloeppel@alumni.uni-kiel.de. ·Hum Pathol · Pubmed #29596894.

ABSTRACT: Pancreatic neuroendocrine carcinoma is a rare aggressive tumor commonly harboring TP53 and RB1 alterations and lacking neuroendocrine-related genetic changes such as mutations in MEN1 and ATRX/DAXX. Little is known about its genetic profile with regard to that of pancreatic ductal adenocarcinoma. We therefore conducted a detailed genetic study in 12 pancreatic neuroendocrine carcinomas of large cell (n = 9) and small cell type (n = 3) using massive parallel sequencing applying a 409-gene panel on an Ion Torrent system. The genetic data were compared with known data of pancreatic ductal adenocarcinoma and correlated with exocrine lineage marker expression. A similar analysis was performed in 11 pancreatic neuroendocrine tumors G3. Neuroendocrine carcinomas harbored 63 somatic mutations in 45 different genes, affecting most commonly TP53 (8/12 cases), KRAS (5/12 cases), and RB1 (loss of expression with or without deletion in 4/12 cases). Five carcinomas had both TP53 and KRAS mutations. Neuroendocrine tumors G3 only shared singular mutations in 5 different genes with neuroendocrine carcinomas, including TP53, CDKN2A, ARID1A, LRP1B, and APC, affecting 5 different cases. Most KRAS-positive neuroendocrine carcinomas also expressed MUC1 (4/5) and carcinoembryonic antigen (3/5) as markers of ductal differentiation. Our data indicate that almost half of the pancreatic neuroendocrine carcinomas are genetically and phenotypically related to pancreatic ductal adenocarcinoma, and might therefore respond to chemotherapies targeting the latter carcinomas.

13 Article None 2018

Iacovazzo, Donato / Flanagan, Sarah E / Walker, Emily / Quezado, Rosana / de Sousa Barros, Fernando Antonio / Caswell, Richard / Johnson, Matthew B / Wakeling, Matthew / Brändle, Michael / Guo, Min / Dang, Mary N / Gabrovska, Plamena / Niederle, Bruno / Christ, Emanuel / Jenni, Stefan / Sipos, Bence / Nieser, Maike / Frilling, Andrea / Dhatariya, Ketan / Chanson, Philippe / de Herder, Wouter W / Konukiewitz, Björn / Klöppel, Günter / Stein, Roland / Korbonits, Márta / Ellard, Sian. ·Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, United Kingdom. · Institute of Biomedical and Clinical Science, University of Exeter Medical School, EX2 5DW Exeter, United Kingdom. · Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232. · Serviço de Endocrinologia e Diabetes, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, 60430-372 Fortaleza, Brazil. · Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzerland. · Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Vienna, A-1090 Vienna, Austria. · Division of Diabetes, Endocrinology and Metabolism, University Hospital of Basel, CH-4031 Basel, Switzerland. · Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Bern, Inselspital, CH-3010 Bern, Switzerland. · Department of Pathology, University of Tübingen, 72076 Tübingen, Germany. · Department of Surgery and Cancer, Imperial College London, W12 0HS London, United Kingdom. · Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, NR4 7UY Norwich, United Kingdom. · Service d'Endocrinologie et des Maladies de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin-Bicêtre, France. · INSERM 1185, Faculté de Médicine Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. · Department of Internal Medicine, Sector of Endocrinology, ENETS Centre of Excellence for Neuroendocrine Tumors, Erasmus MC, 3015 Rotterdam, The Netherlands. · Department of Pathology, Consultation Center for Pancreatic and Endocrine Tumors, Technical University of Munich, 81675 Munich, Germany. · Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, United Kingdom; m.korbonits@qmul.ac.uk. ·Proc Natl Acad Sci U S A · Pubmed #29339498.

ABSTRACT: The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing

14 Article Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model. 2018

Benten, Daniel / Behrang, Yasmin / Unrau, Ludmilla / Weissmann, Victoria / Wolters-Eisfeld, Gerrit / Burdak-Rothkamm, Susanne / Stahl, Felix R / Anlauf, Martin / Grabowski, Patricia / Möbs, Markus / Dieckhoff, Jan / Sipos, Bence / Fahl, Martina / Eggers, Corinna / Perez, Daniel / Bockhorn, Maximillian / Izbicki, Jakob R / Lohse, Ansgar W / Schrader, Jörg. ·I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Gastroenterology, Helios Klinik Duisburg, Duisburg, Germany. · Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of General-, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Institute of Pathology, Limburg, Germany. · Department of Gastroenterology, Rheumatology and Infectious Diseases, Charite Campus Benjamin Franklin, Berlin, Germany. · Institute of Pathology, Charité - Universitaetsmedizin Berlin, Berlin, Germany. · Department for Interventional and Diagnostic Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Pathology, University Hospital Tübingen, Tübingen, Germany. · I. Medical Department - Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. j.schrader@uke.de. ·Mol Cancer Res · Pubmed #29330294.

ABSTRACT: Clinical options for systemic therapy of neuroendocrine tumors (NET) are limited. Development of new drugs requires suitable representative

15 Article ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage. 2017

Perkhofer, Lukas / Schmitt, Anna / Romero Carrasco, Maria Carolina / Ihle, Michaela / Hampp, Stephanie / Ruess, Dietrich Alexander / Hessmann, Elisabeth / Russell, Ronan / Lechel, André / Azoitei, Ninel / Lin, Qiong / Liebau, Stefan / Hohwieler, Meike / Bohnenberger, Hanibal / Lesina, Marina / Algül, Hana / Gieldon, Laura / Schröck, Evelin / Gaedcke, Jochen / Wagner, Martin / Wiesmüller, Lisa / Sipos, Bence / Seufferlein, Thomas / Reinhardt, Hans Christian / Frappart, Pierre-Olivier / Kleger, Alexander. ·Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany. · Department of Internal Medicine, Division I, Hematology/Oncology, Clinical and Molecular Oncology, University Hospital Cologne, Cologne, Germany. · Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany. · Klinik und Poliklinik für Innere Medizin II, Technische Universitaet Muenchen, Munich, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany. · Diabetes Centre, Department of Medicine, University of California at San Francisco, San Francisco, California. · Medical Faculty, Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany. · Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Tuebingen, Germany. · Department of Pathology, University Medical Center Goettingen, Goettingen, Germany. · Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany. · Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany. · Department of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany. · Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany. alexander.kleger@uni-ulm.de pierre.olivier.frappart@uni-ulm.de. ·Cancer Res · Pubmed #28790064.

ABSTRACT: Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional

16 Article Therapeutic effects of Argyrin F in pancreatic adenocarcinoma. 2017

Chen, Xi / Bui, Khac Cuong / Barat, Samarpita / Thi Nguyen, Mai Ly / Bozko, Przemyslaw / Sipos, Bence / Kalesse, Markus / Malek, Nisar P / Plentz, Ruben R. ·Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany. · Institute of Pathology, University of Tübingen, Germany. · Institute of Organic Chemistry & Centre of Biomolecular Drug Research, Leibniz University of Hannover, Germany. · Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany. Electronic address: Ruben.Plentz@med.uni-tuebingen.de. ·Cancer Lett · Pubmed #28408354.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options. The proteasome inhibitor Argyrin A, a cyclic peptide derived from the myxobacterium Archangium gephyra, shows antitumoral activities. We hypothesize that his analogue Argyrin F (AF) may also prevent PDAC progression. We have used PDAC cells and engineered mice (Pdx1-Cre; LSL-KrasG12D; p53

17 Article Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer. 2017

Geismann, Claudia / Grohmann, Frauke / Dreher, Anita / Häsler, Robert / Rosenstiel, Philip / Legler, Karen / Hauser, Charlotte / Egberts, Jan Hendrik / Sipos, Bence / Schreiber, Stefan / Linkermann, Andreas / Hassan, Zonera / Schneider, Günter / Schäfer, Heiner / Arlt, Alexander. ·Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany. · Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, UKSH Campus Kiel, Kiel, Germany. · Department of Surgery, UKSH Campus Kiel, Kiel, German. · Institute of Pathology, University Hospital Tübingen, Tübingen, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany. · Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany. · Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Experimental Cancer Research, UKSH Campus Kiel, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany. Electronic address: aarlt@1med.uni-kiel.de. ·Biochim Biophys Acta Mol Cell Res · Pubmed #28188806.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers. From a clinical view, the transcription factor NF-κB is of particular importance, since this pathway confers apoptosis resistance and limits drug efficacy. Whereas the role of the most abundant NF-κB subunit p65/RelA in therapeutic resistance is well documented, only little knowledge of the RelA downstream targets and their functional relevance in TRAIL mediated apoptosis in PDAC is available. In the present study TRAIL resistant and sensitive PDAC cell lines were analyzed for differentially expressed RelA target genes, to define RelA downstream targets mediating TRAIL resistance. The most upregulated target gene was then further functionally characterized. Unbiased genome-wide expression analysis demonstrated that the chemokine CCL20 represents the strongest TRAIL inducible direct RelA target gene in resistant PDAC cells. Unexpectedly, targeting CCL20 by siRNA, blocking antibodies or by downregulation of the sole CCL20 receptor CCR6 had no effect on PDAC cell death or cancer cell migration, arguing against an autocrine role of CCL20 in PDAC. However, by using an ex vivo indirect co-culture system we were able to show that CCL20 acts paracrine to recruit immune cells. Importantly, CCL20-recruited immune cells further increase TRAIL resistance of CCL20-producing PDAC cells. In conclusion, our data show a functional role of a RelA-CCL20 pathway in PDAC TRAIL resistance. We demonstrate how the therapy-induced cross-talk of cancer cells with immune cells affects treatment responses, knowledge needed to tailor novel bi-specific treatments, which target tumor cell as well as immune cells.

18 Article Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20. 2017

Konukiewitz, Björn / Schlitter, Anna Melissa / Jesinghaus, Moritz / Pfister, Dominik / Steiger, Katja / Segler, Angela / Agaimy, Abbas / Sipos, Bence / Zamboni, Giuseppe / Weichert, Wilko / Esposito, Irene / Pfarr, Nicole / Klöppel, Günter. ·Institute of Pathology, Technical University of Munich, Munich, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital, Erlangen, Germany. · Institute of Pathology, University Hospital of Tuebingen, Tuebingen, Germany. · Institute of Pathology, Sacro Cuore Hospital of Negrar, Verona, Italy. · Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany. ·Mod Pathol · Pubmed #28059098.

ABSTRACT: Somatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index >20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index >20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.

19 Article Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer. 2017

Griesmann, Heidi / Drexel, Christof / Milosevic, Nada / Sipos, Bence / Rosendahl, Jonas / Gress, Thomas M / Michl, Patrick. ·Department of Internal Medicine I, Martin Luther University, Halle, Germany. · Department of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany. · Department of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany. ·Gut · Pubmed #27013602.

ABSTRACT: OBJECTIVES: Tumour-associated macrophages play an important role in mediating tumour progression. In pancreatic cancer, infiltrating macrophages are known to mediate tumour progression and have been identified in invasive tumours and in early preinvasive pancreatic intraepithelial precursor lesions. We aimed to study the impact of pharmacological macrophage depletion by liposomal clodronate in a genetic mouse model of pancreatic cancer. METHODS: KPC mice ( RESULTS: Treatment with liposomal clodronate effectively reduced CD11b-positive macrophages both in the pancreas and other organs such as liver, lung and spleen. While tumour incidence and growth were only slightly reduced, metastasis formation in the liver and lungs was significantly diminished after macrophage depletion. This antimetastatic effect was independent of the presence of an endogenous primary tumour, since reduced pulmonary colonisation was also detected in clodronate-pretreated mice after tail vein injection of syngeneic pancreatic cancer cell lines. Macrophage inhibition by liposomal clodronate was associated with significantly impaired angiogenesis, reduced circulating vascular endothelial growth factor levels and decreased circulating CD4+CD25+ T cells. These alterations could be confirmed in an independent macrophage depletion model using CD11b-diphtheria toxin receptor mice. CONCLUSIONS: Pharmacological depletion of macrophages in a genetic mouse model of pancreatic cancer markedly reduced metastasis formation and is associated with impaired angiogenesis and reduced CD4+CD25+ T cell levels. Pharmacological targeting of infiltrating macrophages represents a promising novel tool for antimetastatic therapeutic approaches.

20 Article Role of BCL9L in transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal-transition (EMT) and metastasis of pancreatic cancer. 2016

Sannino, Giuseppina / Armbruster, Nicole / Bodenhöfer, Mona / Haerle, Ursula / Behrens, Diana / Buchholz, Malte / Rothbauer, Ulrich / Sipos, Bence / Schmees, Christian. ·Natural and Medical Sciences Institute (NMI) at the University of Tuebingen, Tumor Biology Group, Reutlingen, Germany. · Current address: Institute of Pathology, Laboratory of Pediatric Sarcoma Biology, Ludwig-Maximilians-Universität Munich, Munich, Germany. · Current address: Department of Internal Medicine II, University of Tuebingen, Tuebingen, Germany. · Experimental Pharmacology and Oncology GmbH, Berlin, Germany. · Department of Medicine, Division of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Marburg, Germany. · Pharmaceutical Biotechnology, University of Tuebingen, Tuebingen, Germany. · Institute of Pathology, University of Tuebingen, Tuebingen, Germany. ·Oncotarget · Pubmed #27713160.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has a low overall survival rate, which is approximately 20% during the first year and decreases to less than 6% within five years of the disease. This is due to premature dissemination accompanied by a lack of disease-specific symptoms during the initial stages. Additionally, to date there are no biomarkers for an early prognosis available.A growing number of studies indicate that epithelial to mesenchymal transition (EMT), triggered by WNT-, TGF-β- and other signaling pathways is crucial for the initiation of the metastatic process in PDAC. Here we show, that BCL9L is up-regulated in PDAC cell lines and patient tissue compared to non-cancer controls. RNAi-induced BCL9L knockdown negatively affected proliferation, migration and invasion of pancreatic cancer cells. On a molecular basis, BCL9L depletion provoked an increment of E-cadherin protein levels, with concomitant increase of β-catenin retention at the plasma membrane. This is linked to the induction of a strong epithelial phenotype in pancreatic cancer cells upon BCL9L knockdown even in the presence of the EMT-inducer TGF-β. Finally, xenograft mouse models of pancreatic cancer revealed a highly significant reduction in the number of liver metastases upon BCL9L knockdown. Taken together, our findings underline the key importance of BCL9L for EMT and thus progression and metastasis of pancreatic cancer cells. Direct targeting of this protein might be a valuable approach to effectively antagonize invasion and metastasis of PDAC.

21 Article Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model. 2016

Hidalgo-Sastre, Ana / Brodylo, Roxanne L / Lubeseder-Martellato, Clara / Sipos, Bence / Steiger, Katja / Lee, Marcel / von Figura, Guido / Grünwald, Barbara / Zhong, Suyang / Trajkovic-Arsic, Marija / Neff, Florian / Schmid, Roland M / Siveke, Jens T. ·II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Pathology, University Hospital Tübingen, Tübingen, Germany. · Comparative Experimental Pathology Unit, Institute for General Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany. · Institute of Molecular Immunology and Experimental Oncology, Technical University of Munich, Munich, Germany. · German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany. · II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. Electronic address: j.siveke@dkfz.de. ·Am J Pathol · Pubmed #27639167.

ABSTRACT: Perturbation of pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a

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

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

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

23 Article miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer. 2016

Mühlberg, Leonie / Kühnemuth, Benjamin / Costello, Eithne / Shaw, Victoria / Sipos, Bence / Huber, Magdalena / Griesmann, Heidi / Krug, Sebastian / Schober, Marvin / Gress, Thomas M / Michl, Patrick. ·Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University , Marburg, Germany. · Department of Surgery, University of Liverpool , Liverpool, UK. · Institute of Pathology, University of Tuebingen , Tuebingen, Germany. · Institute of Microbiology, University Hospital, Philipps-University , Marburg, Germany. · Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg , Halle, Germany. · Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University, Marburg, Germany; Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle, Germany. ·Oncoimmunology · Pubmed #27471627.

ABSTRACT: Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu.

24 Article RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis. 2016

Lesina, Marina / Wörmann, Sonja Maria / Morton, Jennifer / Diakopoulos, Kalliope Nina / Korneeva, Olga / Wimmer, Margit / Einwächter, Henrik / Sperveslage, Jan / Demir, Ihsan Ekin / Kehl, Timo / Saur, Dieter / Sipos, Bence / Heikenwälder, Mathias / Steiner, Jörg Manfred / Wang, Timothy Cragin / Sansom, Owen J / Schmid, Roland Michael / Algül, Hana. · ·J Clin Invest · Pubmed #27454298.

ABSTRACT: Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.

25 Article Membranous CD24 drives the epithelial phenotype of pancreatic cancer. 2016

Lubeseder-Martellato, Clara / Hidalgo-Sastre, Ana / Hartmann, Carolin / Alexandrow, Katharina / Kamyabi-Moghaddam, Zahra / Sipos, Bence / Wirth, Matthias / Neff, Florian / Reichert, Maximilian / Heid, Irina / Schneider, Günter / Braren, Rickmer / Schmid, Roland M / Siveke, Jens T. ·II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Current address: Klinik für Anaesthesiologie, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Institute of Pathology, University Tübingen, Tübingen, Germany. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Institute of Radiology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. ·Oncotarget · Pubmed #27203385.

ABSTRACT: Surface CD24 has previously been described, together with CD44 and ESA, for the characterization of putative cancer stem cells in pancreatic ductal adenocarcinoma (PDAC), the most fatal of all solid tumors. CD24 has a variety of biological functions including the regulation of invasiveness and cell proliferation, depending on the tumor entity and subcellular localization. Genetically engineered mouse models (GEMM) expressing oncogenic KrasG12D recapitulate the human disease and develop PDAC. In this study we investigate the function of CD24 using GEMM of endogenous PDAC and a model of cerulein-induced acute pancreatitis. We found that (i) CD24 expression was upregulated in murine and human PDAC and during acute pancreatitis (ii) CD24 was expressed exclusively in differentiated PDAC, whereas CD24 absence was associated with undifferentiated tumors and (iii) membranous CD24 expression determines tumor subpopulations with an epithelial phenotype in grafted models. In addition, we show that CD24 protein is stabilized in response to WNT activation and that overexpression of CD24 in pancreatic cancer cells upregulated β-catenin expression augmenting an epithelial, non-metastatic signature. Our results support a positive feedback model according to which (i) WNT activation and subsequent β-catenin dephosphorylation stabilize CD24 protein expression, and (ii) sustained CD24 expression upregulates β-catenin expression. Eventually, membranous CD24 augments the epithelial phenotype of pancreatic tumors. Thus we link the WNT/β-catenin pathway with the regulation of CD24 in the context of PDAC differentiation.

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