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Pancreatic Neoplasms: HELP
Articles by Susanne Raulefs
Based on 12 articles published since 2010
(Why 12 articles?)
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Between 2010 and 2020, Susanne Raulefs wrote the following 12 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Energy metabolism and proliferation in pancreatic carcinogenesis. 2012

Regel, Ivonne / Kong, Bo / Raulefs, Susanne / Erkan, Mert / Michalski, Christoph W / Hartel, Mark / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Ismaningerstrasse 22, 81675 Munich, Germany. ·Langenbecks Arch Surg · Pubmed #22430298.

ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer entity with a high proliferative potential. Uncontrolled cell proliferation is mediated by a number of core signaling pathways. Recently, novel data of PDAC biology suggest that these core signal pathways affect cell proliferation and metabolism simultaneously. METHODS: Here, we reviewed the literature on core metabolic signaling pathways in pancreatic carcinogenesis. RESULTS: Results obtained from mouse genetics and in vitro experiments have demonstrated the significance of the Kras, p53, c-Myc, and Lkb1 networks in the proliferation of pancreatic epithelial and cancer cells. At the same time, these major pathways also affect energy metabolism by influencing glucose and glutamine utilization. In particular, Kras-mediated metabolic changes seem to be directly involved in carcinogenesis. However, there is a lack of solid evidence on how metabolism and proliferation are connected in pancreatic carcinogenesis. CONCLUSION: Understanding early and subtle changes in cellular metabolism of pancreatic epithelial-and specifically of acinar-cells, which accompany or directly influence malignant transformation and uncontrolled proliferation, will be paramount to define novel imaging and other modalities for earlier detection of PDAC.

2 Article Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis. 2019

Benitz, Simone / Straub, Tobias / Mahajan, Ujjwal Mukund / Mutter, Jurik / Czemmel, Stefan / Unruh, Tatjana / Wingerath, Britta / Deubler, Sabrina / Fahr, Lisa / Cheng, Tao / Nahnsen, Sven / Bruns, Philipp / Kong, Bo / Raulefs, Susanne / Ceyhan, Güralp O / Mayerle, Julia / Steiger, Katja / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W / Regel, Ivonne. ·Department of Medicine II, University Hospital, LMU Munich, Munich, Germany. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA. · Bioinformatic Unit, Biomedical Center, Faculty of Medicine, LMU Munich, Munich, Germany. · Quantitative Biology Center, University of Tuebingen, Tuebingen, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital, Duesseldorf, Germany. · Department of Surgery, Technical University Munich, Munich, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · Institute of Pathology, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany. · Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany. ·Gut · Pubmed #30954952.

ABSTRACT: BACKGROUND AND AIMS: Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis. DESIGN: With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells. RESULTS: The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype. CONCLUSIONS: Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.

3 Article Ductal obstruction promotes formation of preneoplastic lesions from the pancreatic ductal compartment. 2019

Cheng, Tao / Zhang, Zhiheng / Jian, Ziying / Raulefs, Susanne / Schlitter, Anna Melissa / Steiger, Katja / Maeritz, Nadja / Zhao, Yamin / Shen, Shanshan / Zou, Xiaoping / Ceyhan, Güralp O / Friess, Helmut / Kleeff, Jörg / Michalski, Christoph W / Kong, Bo. ·Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · German Cancer Consortium (DKTK) at the partner site Munich, Munich, Germany. · Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany. ·Int J Cancer · Pubmed #30412288.

ABSTRACT: Pancreatitis is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice have demonstrated that pancreatitis contributes to oncogenic Kras-driven carcinogenesis, probably initiated in acinar cells; however, oncogenic Kras alone or in combination with caerulein-induced pancreatitis is not sufficient in initiating PDAC from the ductal compartment. We thus introduced ductal obstruction - which induces a more severe form of pancreatitis - by pancreatic ductal ligation in mice harbouring oncogenic Kras. This induced a particular phenotype with highly proliferative nonmucinous cells with nuclear atypia. Around these lesions, there was a significant proliferation of activated fibroblasts and infiltration of immune cells, corroborating the pathological features of preneoplastic lesions. Lineage-tracing experiments revealed that these preneoplastic cells derived from two distinctive cellular sources: acinar and ductal cells. Phenotypic characterisation revealed that the duct-derived preneoplastic lesions show a high proliferative potential with persistent activation of tumour-promoting inflammatory pathways while the acinar-derived ones were less proliferative with persistent p53 activation. Furthermore, the duct-derived preneoplastic cells have a particularly high nuclear-to-cytoplasmic ratio. These data demonstrate that ductal obstruction promotes preneoplastic lesion formation from the pancreatic ductal compartment.

4 Article Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma. 2018

Jian, Ziying / Cheng, Tao / Zhang, Zhiheng / Raulefs, Susanne / Shi, Kuangyu / Steiger, Katja / Maeritz, Nadja / Kleigrewe, Karin / Hofmann, Thomas / Benitz, Simone / Bruns, Philipp / Lamp, Daniel / Jastroch, Martin / Akkan, Jan / Jäger, Carsten / Huang, Peilin / Nie, Shuang / Shen, Shanshan / Zou, Xiaoping / Ceyhan, Güralp O / Michalski, Christoph W / Friess, Helmut / Kleeff, Jörg / Kong, Bo. ·Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany. · Department of Nuclear Medicine, TUM, Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Bavarian Center for Biomolecular Mass Spectrometry, Freising, Germany. · Medizinische Klinik und Poliklinik II, Klinikum der LMU, Munich, Germany. · Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany. · Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. · German Center for Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany. · Division of Metabolic Diseases, TUM, Munich, Germany. · Department of Pathology, School of Medicine, Southeast University, Nanjing, China. · Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany. · German Cancer Consortium (DKTK) at the partner site Munich, Munich, Germany. ·Cell Mol Gastroenterol Hepatol · Pubmed #30258965.

ABSTRACT: Background & Aims: Although nearly half of pancreatic ductal adenocarcinoma (PDAC) patients have diabetes mellitus with episodes of hyperglycemia, its tumor microenvironment is hypoglycemic. Thus, it is crucial for PDAC cells to develop adaptive mechanisms dealing with oscillating glucose levels. So far, the biological impact of such glycemic variability on PDAC biology remains unknown. Methods: Murine PDAC cells were cultured in low- and high-glucose medium to investigate the molecular, biochemical, and metabolic influence of glycemic variability on tumor behavior. A set of in vivo functional assays including orthotopic implantation and portal and tail vein injection were used. Results were further confirmed on tissues from PDAC patients. Results: Glycemic variability has no significant effect on PDAC cell proliferation. Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization. Increased metastatic colonization under hyperglycemia is due to increased expression of runt related transcription factor 3 (Runx3), which further activates expression of collagen, type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic pathway. Through epigenetic machinery, retinoic acid receptor beta (Rarb) expression fluctuates according to glycemic variability, acting as a critical sensor relaying the glycemic signal to Runx3/Col6a1. Moreover, the signal axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to a widely used antidiabetic substance, metformin, and Rar modulator. Finally, PDAC tissues from patients with diabetes show an increased expression of COL6A1. Conclusions: Glycemic variability promotes both local invasion and metastatic colonization of PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose activity is controlled by glycemic variability is identified. The therapeutic relevance of this pathway needs to be explored in PDAC patients, especially in those with diabetes.

5 Article Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy. 2018

Kong, Bo / Bruns, Philipp / Behler, Nora A / Chang, Ligong / Schlitter, Anna Melissa / Cao, Jing / Gewies, Andreas / Ruland, Jürgen / Fritzsche, Sina / Valkovskaya, Nataliya / Jian, Ziying / Regel, Ivonne / Raulefs, Susanne / Irmler, Martin / Beckers, Johannes / Friess, Helmut / Erkan, Mert / Mueller, Nikola S / Roth, Susanne / Hackert, Thilo / Esposito, Irene / Theis, Fabian J / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Department of Gastroenterology, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, China. · Institute of Computational Biology, Helmholtz-Zentrum München GmbH, Neuherberg, Germany. · Institute of Pathology, TUM, Munich, Germany. · Institute für Klinische Chemie und Pathobiochemie, TUM, Munich, Germany. · Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Neuherberg, Germany. · German Cancer Consortium (DKTK) at the partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany. · German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. · Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany. · Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany. · Chair of Experimental Genetics, Technische Universität München, Freising, Germany. · Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany. · Department of Surgery, Koc University, Istanbul, Turkey. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Mathematics, TUM, Munich, Germany. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. ·Gut · Pubmed #27646934.

ABSTRACT: OBJECTIVE: The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined. DESIGN: We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated Kras RESULTS: We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer. CONCLUSIONS: These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.

6 Article Polycomb repressor complex 1 promotes gene silencing through H2AK119 mono-ubiquitination in acinar-to-ductal metaplasia and pancreatic cancer cells. 2016

Benitz, Simone / Regel, Ivonne / Reinhard, Tobias / Popp, Anna / Schäffer, Isabell / Raulefs, Susanne / Kong, Bo / Esposito, Irene / Michalski, Christoph W / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Munich, Germany. · Institute of Pathology, Heinrich-Heine University, Duesseldorf, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · The Royal Liverpool and Broadgreen University Hospitals, Liverpool, United Kingdom. · Department of Surgery, Heinrich-Heine University, Duesseldorf, Germany. ·Oncotarget · Pubmed #26716510.

ABSTRACT: Acinar-to-ductal metaplasia (ADM) occurring in cerulein-mediated pancreatitis or in oncogenic Kras-driven pancreatic cancer development is accompanied by extensive changes in the transcriptional program. In this process, acinar cells shut down the expression of acinar specific differentiation genes and re-express genes usually found in embryonic pancreatic progenitor cells. Previous studies have demonstrated that a loss of acinar-specific transcription factors sensitizes the cells towards oncogenic transformation, ultimately resulting in cancer development. However, the mechanism behind the transcriptional silencing of acinar cell fate genes in ADM and pancreatic cancer is largely unknown. Here, we analyzed whether elevated levels of the polycomb repressor complex 1 (PRC1) components Bmi1 and Ring1b and their catalyzed histone modification H2AK119ub in ADMs and tumor cells, are responsible for the mediation of acinar gene silencing. Therefore, we performed chromatin-immunoprecipitation in in vitro generated ADMs and isolated murine tumor cells against the repressive histone modifications H3K27me3 and H2AK119ub. We established that the acinar transcription factor complex Ptf1-L is epigenetically silenced in ADMs as well as in pancreatic tumor cells. For the first time, this work presents a possible mechanism of acinar gene silencing, which is an important prerequisite in the initiation and maintenance of a dedifferentiated cell state in ADMs and tumor cells.

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

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

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

8 Article Pancreas-specific activation of mTOR and loss of p53 induce tumors reminiscent of acinar cell carcinoma. 2015

Kong, Bo / Cheng, Tao / Qian, Chengjia / Wu, Weiwei / Steiger, Katja / Cao, Jing / Schlitter, Anna Melissa / Regel, Ivonne / Raulefs, Susanne / Friess, Helmut / Erkan, Mert / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Institute of Pathology, TUM, Munich, Germany. · Department of Surgery, Koc School of Medicine, Istanbul, Turkey. · Institute of Pathology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. · Royal Liverpool and Broadgreen University Hospitals, Liverpool, UK. · Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. cwmichalski@gmail.com. ·Mol Cancer · Pubmed #26683340.

ABSTRACT: BACKGROUND: Pancreatic acinar cell carcinoma (ACC) is a rare tumor entity with an unfavorable prognosis. Recent whole-exome sequencing identified p53 mutations in a subset of human ACC. Activation of the mammalian target of rapamycin (mTOR) pathway is associated with various pancreatic neoplasms. We thus aimed at analyzing whether activation of mTOR with a concomitant loss of p53 may initiate ACC. METHODS: We generated transgenic mouse models in which mTOR was hyperactivated through pancreas-specific, homozygous tuberous sclerosis 1 (Tsc1) deficiency, with or without deletion of p53 (Tsc1 (-/-) and Tsc1 (-/-) ; p53 (-/-) ). Activity of mTOR signaling was investigated using mouse tissues and isolated murine cell lines. Human ACC specimens were used to corroborate the findings from the transgenic mouse models. RESULTS: Hyperactive mTOR signaling in Tsc1 (-/-) mice was not oncogenic but rather induced a near-complete loss of the pancreatic acinar compartment. Acinar cells were lost as a result of apoptosis which was associated with p53 activation. Concomitantly, ductal cells were enriched. Ablation of p53 in Tsc1-deficient mice prevented acinar cell death but promoted formation of acinar cells with severe nuclear abnormalities. One out of seven Tsc1 (-/-) ; p53 (-/-) animals developed pancreatic tumors showing a distinctive tumor morphology, reminiscent of human ACC. Hyperactive mTOR signaling was also detected in a subset of human ACC. CONCLUSION: Hyperactive mTOR signaling combined with loss of p53 in mice induces tumors similar to human ACC.

9 Article Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer. 2015

Kong, Bo / Cheng, Tao / Wu, Weiwei / Regel, Ivonne / Raulefs, Susanne / Friess, Helmut / Erkan, Mert / Esposito, Irene / Kleeff, Jörg / Michalski, Christoph W. ·Department of Surgery, Technische Universität München (TUM), Munich, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Institute of Pathology, Medical University Innsbruck, Innsbruck, Austria. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Oncotarget · Pubmed #26452217.

ABSTRACT: Stromal fibrosis and tissue necrosis are major histological sequelae of hypoxia. The hypoxia-to-fibrosis sequence is well-documented in pancreatic ductal adenocarcinoma (PDAC). However, hypoxic and necrotic PDAC phenotypes are insufficiently characterized. Recently, reduction of tuberous sclerosis expression in mice together with oncogenic Kras demonstrated a rapidly metastasizing phenotype with histologically eccentric necrosis, transitional hypoxia and devascularisation. We established cell lines from these tumors and transplanted them orthotopically into wild-type mice to test their abilities to recapitulate the histological features of the primary lesions. Notably, the necrotic phenotype was reproduced by only a subset of cell lines while others gave rise to dedifferentiated tumors with significantly reduced necrosis. In vitro analysis of the necrotic tumor-inducing cell lines revealed that these cells released a significant amount of vascular endothelial growth factor A (Vegfa). However, its release was not further increased under hypoxic conditions. Defective hypoxia-induced Vegfa secretion was not due to impaired Vegfa transcription or hypoxia-inducible factor 1-alpha activation, but rather a result of hypoxia-induced endoplasmic reticulum (ER) stress. We thus identified hypoxia-induced ER stress as an important pathway in PDACs with tissue necrosis and rapid metastasis.

10 Article Kif20a inhibition reduces migration and invasion of pancreatic cancer cells. 2015

Stangel, Daniela / Erkan, Mert / Buchholz, Malte / Gress, Thomas / Michalski, Christoph / Raulefs, Susanne / Friess, Helmut / Kleeff, Jörg. ·Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; Department of Surgery, Koc School of Medicine, Istanbul, Turkey. Electronic address: m.mert.erkan@googlemail.com. · Department of Gastroenterology and Endocrinology, University Hospital, Philipps-University, Marburg, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·J Surg Res · Pubmed #25953216.

ABSTRACT: BACKGROUND: The Translational Genome Research Network in Pancreatic Cancer performed a meta-analysis of publicly available various high-throughput gene analysis panels to identify drugable targets. There, the most differentially expressed gene between normal and cancerous pancreas was Kif20a. The aim of the study was to verify this expression pattern and further characterize Kif20a in pancreatic cancer. MATERIALS AND METHODS: Detailed expression analyses were carried out in pancreatic tissues and in a wide panel of pancreatic cells including ductal adenocarcinoma (PDAC) and neuroendocrine-cancer cell lines as well as immortalized human pancreatic ductal epithelial and primary stellate cells using quantitative real-time polymerase chain reaction, immunohistochemistry, immunofluorescence, and immunoblot analyses. Effects on proliferation, apoptosis, and cell cycle were assessed by MTT assays, caspase-cleavage assays, and fluorescence-activated cell sorting analysis after Kif20a silencing. Cell motility was assessed by migration and invasion assays as well as time-lapse microscopy. RESULTS: Mean Kif20a messenger RNA expression was 18.4-fold upregulated in PDAC tissues compared with that in the normal pancreas. In line, neuroendocrine-cancer cell lines display a 1.6-fold increase and ductal adenocarcinoma cell lines a 11-fold increase of Kif20a messenger RNA (P = 0.009) in comparison with primary stellate cells. A 7.3-fold overexpression was also found in immortalized pancreatic ductal epithelial cells. Kif20a silencing with small interfering RNA molecules resulted in an inhibition of proliferation, motility, and invasion of pancreatic cancer cell lines. CONCLUSIONS: Targeting Kif20a reduces proliferation, migration, and invasion of pancreatic cancer cells. Together with its significant overexpression in PDAC, this makes it a potential target for diagnostic and interventional purposes.

11 Article Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer. 2015

Müller, Sören / Raulefs, Susanne / Bruns, Philipp / Afonso-Grunz, Fabian / Plötner, Anne / Thermann, Rolf / Jäger, Carsten / Schlitter, Anna Melissa / Kong, Bo / Regel, Ivonne / Roth, W Kurt / Rotter, Björn / Hoffmeier, Klaus / Kahl, Günter / Koch, Ina / Theis, Fabian J / Kleeff, Jörg / Winter, Peter / Michalski, Christoph W. ·Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · Molecular Bioinformatics Group, Institute of Computer Science, Cluster of Excellence Frankfurt 'Macromolecular Complexes' Faculty of Computer Science and Mathematics, Frankfurt am Main, Germany. s.mueller@bio.uni-frankfurt.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. susanne.raulefs@tum.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. philipp.bruns@helmholtz-muenchen.de. · Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. fgrunz@stud.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. fgrunz@stud.uni-frankfurt.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. ploetner@genxpro.de. · GFE Blut mbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. rolf.thermann@gfeblut.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. Carsten.Jaeger@lrz.tu-muenchen.de. · Department of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. melissa.schlitter@lrz.tu-muenchen.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. kongbo81@hotmail.com. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. ivonne.regel@lrz.tum.de. · GFE Blut mbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. kurt.roth@gfeblut.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. rotter@genxpro.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. hoffmeier@genxpro.de. · Molecular BioSciences, Goethe University, Frankfurt am Main, Germany. kahl@em.uni-frankfurt.de. · Molecular Bioinformatics Group, Institute of Computer Science, Cluster of Excellence Frankfurt 'Macromolecular Complexes' Faculty of Computer Science and Mathematics, Frankfurt am Main, Germany. ina.koch@bioinformatik.uni-frankfurt.de. · Institute of Computational Biology, Helmholtz Zentrum Munich, Neuherberg, Germany. fabian.theis@helmholtz-muenchen.de. · Department of Mathematics, TU Munich, Boltzmannstrasse 3, Garching, Germany. fabian.theis@helmholtz-muenchen.de. · Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. kleeff@tum.de. · GenXPro GmbH, Frankfurt Biotechnology Innovation Center, Frankfurt am Main, Germany. pwinter@genxpro.de. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. cwmichalski@gmail.com. ·Mol Cancer · Pubmed #25910082.

ABSTRACT: BACKGROUND: Previous studies identified microRNAs (miRNAs) and messenger RNAs with significantly different expression between normal pancreas and pancreatic cancer (PDAC) tissues. Due to technological limitations of microarrays and real-time PCR systems these studies focused on a fixed set of targets. Expression of other RNA classes such as long intergenic non-coding RNAs or sno-derived RNAs has rarely been examined in pancreatic cancer. Here, we analysed the coding and non-coding transcriptome of six PDAC and five control tissues using next-generation sequencing. RESULTS: Besides the confirmation of several deregulated mRNAs and miRNAs, miRNAs without previous implication in PDAC were detected: miR-802, miR-2114 or miR-561. SnoRNA-derived RNAs (e.g. sno-HBII-296B) and piR-017061, a piwi-interacting RNA, were found to be differentially expressed between PDAC and control tissues. In silico target analysis of miR-802 revealed potential binding sites in the 3' UTR of TCF4, encoding a transcription factor that controls Wnt signalling genes. Overexpression of miR-802 in MiaPaCa pancreatic cancer cells reduced TCF4 protein levels. Using Massive Analysis of cDNA Ends (MACE) we identified differential expression of 43 lincRNAs, long intergenic non-coding RNAs, e.g. LINC00261 and LINC00152 as well as several natural antisense transcripts like HNF1A-AS1 and AFAP1-AS1. Differential expression was confirmed by qPCR on the mRNA/miRNA/lincRNA level and by immunohistochemistry on the protein level. CONCLUSIONS: Here, we report a novel lncRNA, sncRNA and mRNA signature of PDAC. In silico prediction of ncRNA targets allowed for assigning potential functions to differentially regulated RNAs.

12 Article Syndecan-2 promotes perineural invasion and cooperates with K-ras to induce an invasive pancreatic cancer cell phenotype. 2012

De Oliveira, Tiago / Abiatari, Ivane / Raulefs, Susanne / Sauliunaite, Danguole / Erkan, Mert / Kong, Bo / Friess, Helmut / Michalski, Christoph W / Kleeff, Jörg. ·Department of Surgery, Technische Universität München, Munich, Germany. ·Mol Cancer · Pubmed #22471946.

ABSTRACT: BACKGROUND: We have identified syndecan-2 as a protein potentially involved in perineural invasion of pancreatic adenocarcinoma (PDAC) cells. METHODS: Syndecan-2 (SDC-2) expression was analyzed in human normal pancreas, chronic pancreatitis and PDAC tissues. Functional in vitro assays were carried out to determine its role in invasion, migration and signaling. RESULTS: SDC-2 was expressed in the majority of the tested pancreatic cancer cell lines while it was upregulated in nerve-invasive PDAC cell clones. There were 2 distinct expression patterns of SDC-2 in PDAC tissue samples: SDC-2 positivity in the cancer cell cytoplasm and a peritumoral expression. Though SDC-2 silencing (using specific siRNA oligonucleotides) did not affect anchorage-dependent growth, it significantly reduced cell motility and invasiveness in the pancreatic cancer cell lines T3M4 and Su8686. On the transcriptional level, migration-and invasion-associated genes were down-regulated following SDC-2 RNAi. Furthermore, SDC-2 silencing reduced K-ras activity, phosphorylation of Src and--further downstream--phosphorylation of ERK2 while levels of the putative SDC-2 signal transducer p120GAP remained unaltered. CONCLUSION: SDC-2 is a novel (perineural) invasion-associated gene in PDAC which cooperates with K-ras to induce a more invasive phenotype.