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Pancreatic Neoplasms: HELP
Articles by Dieter Saur
Based on 34 articles published since 2010
(Why 34 articles?)
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Between 2010 and 2020, D. Saur wrote the following 34 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Oncogenic KRAS and the EGFR loop in pancreatic carcinogenesis-A connection to licensing nodes. 2018

Schneeweis, Christian / Wirth, Matthias / Saur, Dieter / Reichert, Maximilian / Schneider, Günter. ·a II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München , München , Germany. · b German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) , Heidelberg , Germany. ·Small GTPases · Pubmed #27880072.

ABSTRACT: EGFR signaling has a critical role in oncogenic KRAS-driven tumorigenesis of the pancreas, whereas it is dispensable in other organs. The complex signaling network engaged by oncogenic KRAS and its modulation by EGFR signaling, remains incompletely understood. In order to study early signaling events activated by oncogenic KRAS in the pancreas, we recently developed a novel model system based on murine primary pancreatic epithelial cells enabling the time-specific expression of mutant Kras

2 Review Oncogenic KRAS signalling in pancreatic cancer. 2014

Eser, S / Schnieke, A / Schneider, G / Saur, D. ·1] Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. · Livestock Biotechnology, Technische Universität München, Liesel-Beckmann Str. 1., 85354 Freising, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany. ·Br J Cancer · Pubmed #24755884.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.

3 Review Acetylation as a transcriptional control mechanism-HDACs and HATs in pancreatic ductal adenocarcinoma. 2011

Schneider, Günter / Krämer, Oliver H / Schmid, Roland M / Saur, Dieter. ·Klinikum rechts der Isar, II. Medizinische Klinik, Technische Universität München, Ismaninger Strasse 22, Munich, Germany. guenter.schneider@lrz.tum.de ·J Gastrointest Cancer · Pubmed #21271301.

ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis. Although our understanding of the carcinogenesis of the disease increases continuously, no effective conservative therapeutic strategies exist. Therefore, novel targets have to be defined at the experimental level. Histone deacetylases (HDACs), especially the class I isoenzymes HDAC1, 2, and 3, are highly expressed in PDAC. CONCLUSION: This article summarizes the expression and functions of HDAC isoenzymes in PDAC, with a special focus on their promoter-specific mode of action. Although we have gained some molecular insight into the HDAC function in PDAC, less is known about the relevance of histone acetyltransferases (HATs) in PDAC. As an example, we will summarize function of the HAT p300, for which promoter-specific functions were described recently. Increasing the molecular insights into the functions of the acetylating and deacetylating machineries in PDAC are important, since this will lead to novel rationally based therapeutic strategies in the future.

4 Article A Yap-Myc-Sox2-p53 Regulatory Network Dictates Metabolic Homeostasis and Differentiation in Kras-Driven Pancreatic Ductal Adenocarcinomas. 2019

Murakami, Shigekazu / Nemazanyy, Ivan / White, Shannon M / Chen, Hengye / Nguyen, Chan D K / Graham, Garrett T / Saur, Dieter / Pende, Mario / Yi, Chunling. ·Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. · Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, Institut Necker Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Division of Translational Cancer Research, Heidelberg, Germany. · Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. Electronic address: cy232@georgetown.edu. ·Dev Cell · Pubmed #31447265.

ABSTRACT: Employing inducible genetically engineered and orthotopic mouse models, we demonstrate a key role for transcriptional regulator Yap in maintenance of Kras-mutant pancreatic tumors. Integrated transcriptional and metabolomics analysis reveals that Yap transcribes Myc and cooperates with Myc to maintain global transcription of metabolic genes. Yap loss triggers acute metabolic stress, which causes tumor regression while inducing epigenetic reprogramming and Sox2 upregulation in a subset of pancreatic neoplastic cells. Sox2 restores Myc expression and metabolic homeostasis in Yap-deficient neoplastic ductal cells, which gradually re-differentiate into acinar-like cells, partially restoring pancreatic parenchyma in vivo. Both the short-term and long-term effects of Yap loss in inducing cell death and re-differentiation, respectively, are blunted in advanced, poorly differentiated p53-mutant pancreatic tumors. Collectively, these findings reveal a highly dynamic and interdependent metabolic, transcriptional, and epigenetic regulatory network governed by Yap, Myc, Sox2, and p53 that dictates pancreatic tumor metabolism, growth, survival, and differentiation.

5 Article Metastasis of pancreatic cancer: An uninflamed liver micromilieu controls cell growth and cancer stem cell properties by oxidative phosphorylation in pancreatic ductal epithelial cells. 2019

Fabian, Alexander / Stegner, Simon / Miarka, Lauritz / Zimmermann, Johannes / Lenk, Lennart / Rahn, Sascha / Buttlar, Jann / Viol, Fabrice / Knaack, Hendrike / Esser, Daniela / Schäuble, Sascha / Großmann, Peter / Marinos, Georgios / Häsler, Robert / Mikulits, Wolfgang / Saur, Dieter / Kaleta, Christoph / Schäfer, Heiner / Sebens, Susanne. ·Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105, Kiel, Germany. · Group Medical Systems Biology, Institute for Experimental Medicine, Michaelisstr. 5, Building 17, 24105, Kiel, Germany. · Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Schwanenweg 20, 24105, Kiel, Germany. · Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Beutenbergstraße 11A, 07745, Jena, Germany. · Group Molecular Cell Biology, Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Rosalind-Franklin-Straße 12, 24105, Kiel, Germany. · Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. · II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein (UKSH) Campus Kiel, Arnold-Heller-Str. 3, Building 17, 24105, Kiel, Germany. Electronic address: susanne.sebens@email.uni-kiel.de. ·Cancer Lett · Pubmed #30930235.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed when liver metastases already emerged. We recently demonstrated that hepatic stromal cells determine the dormancy status along with cancer stem cell (CSC) properties of pancreatic ductal epithelial cells (PDECs) during metastasis. This study investigated the influence of the hepatic microenvironment - and its inflammatory status - on metabolic alterations and how these impact cell growth and CSC-characteristics of PDECs. Coculture with hepatic stellate cells (HSCs), simulating a physiological liver stroma, but not with hepatic myofibroblasts (HMFs) representing liver inflammation promoted expression of Succinate Dehydrogenase subunit B (SDHB) and an oxidative metabolism along with a quiescent phenotype in PDECs. SiRNA-mediated SDHB knockdown increased cell growth and CSC-properties. Moreover, liver micrometastases of tumor bearing KPC mice strongly expressed SDHB while expression of the CSC-marker Nestin was exclusively found in macrometastases. Consistently, RNA-sequencing and in silico modeling revealed significantly altered metabolic fluxes and enhanced SDH activity predominantly in premalignant PDECs in the presence of HSC compared to HMF. Overall, these data emphasize that the hepatic microenvironment determines the metabolism of disseminated PDECs thereby controlling cell growth and CSC-properties during liver metastasis.

6 Article Dual reporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program. 2018

Chen, Yang / LeBleu, Valerie S / Carstens, Julienne L / Sugimoto, Hikaru / Zheng, Xiaofeng / Malasi, Shruti / Saur, Dieter / Kalluri, Raghu. ·Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Medicine II Klinikum rechts der Isar, Technische Universität München, München, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. · Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA rkalluri@mdanderson.org. ·EMBO Mol Med · Pubmed #30120146.

ABSTRACT: Epithelial-to-mesenchymal transition (EMT) is a recognized eukaryotic cell differentiation program that is also observed in association with invasive tumors. Partial EMT program in carcinomas imparts cancer cells with mesenchymal-like features and is proposed as essential for metastasis. Precise determination of the frequency of partial EMT program in cancer cells in tumors and its functional role in metastases needs unraveling. Here, we employed mesenchymal cell reporter mice driven by

7 Article The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. 2018

Tsuda, Motoyuki / Fukuda, Akihisa / Roy, Nilotpal / Hiramatsu, Yukiko / Leonhardt, Laura / Kakiuchi, Nobuyuki / Hoyer, Kaja / Ogawa, Satoshi / Goto, Norihiro / Ikuta, Kozo / Kimura, Yoshito / Matsumoto, Yoshihide / Takada, Yutaka / Yoshioka, Takuto / Maruno, Takahisa / Yamaga, Yuichi / Kim, Grace E / Akiyama, Haruhiko / Ogawa, Seishi / Wright, Christopher V / Saur, Dieter / Takaori, Kyoichi / Uemoto, Shinji / Hebrok, Matthias / Chiba, Tsutomu / Seno, Hiroshi. ·Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Diabetes Center, Department of Medicine, UCSF, San Francisco, California, USA. · Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Hematology, Oncology and Tumorimmunology, Charite-Universitätsmedizin Berlin, Berlin, Germany. · Department of Pathology, UCSF, San Francisco, California, USA. · Department of Orthopaedics, Gifu University, Gifu, Japan. · Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. · Department of Internal Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Kansai Electric Power Hospital, Osaka, Japan. ·J Clin Invest · Pubmed #30010625.

ABSTRACT: Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.

8 Article Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer. 2018

Reichert, Maximilian / Bakir, Basil / Moreira, Leticia / Pitarresi, Jason R / Feldmann, Karin / Simon, Lauren / Suzuki, Kensuke / Maddipati, Ravikanth / Rhim, Andrew D / Schlitter, Anna M / Kriegsmann, Mark / Weichert, Wilko / Wirth, Matthias / Schuck, Kathleen / Schneider, Günter / Saur, Dieter / Reynolds, Albert B / Klein-Szanto, Andres J / Pehlivanoglu, Burcin / Memis, Bahar / Adsay, N Volkan / Rustgi, Anil K. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University Munich, Medizinische Klinik, Ismaninger Str. 22, Munich 81675, Germany. Electronic address: maximilian.reichert@tum.de. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Catalonia, Spain. · Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University Munich, Medizinische Klinik, Ismaninger Str. 22, Munich 81675, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. · Division of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, TX, USA. · Institute of General Pathology and Pathological Anatomy, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. · Institute of Pathology, Heidelberg University, Heidelberg, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, Düsseldorf 40225, Germany. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, USA. · Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA. · Department of Pathology, Koc University Hospital, Istanbul, Turkey. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 900 Biomedical Research Building II/III, 415 Curie Boulevard, Philadelphia, PA 19104, USA. Electronic address: anil2@pennmedicine.upenn.edu. ·Dev Cell · Pubmed #29920275.

ABSTRACT: The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin (p120ctn)-mediated epithelial identity. Mono-allelic p120ctn loss accelerates Kras

9 Article Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting. 2018

Cheung, Phyllis F / Neff, Florian / Neander, Christian / Bazarna, Anna / Savvatakis, Konstantinos / Liffers, Sven-Thorsten / Althoff, Kristina / Lee, Chang-Lung / Moding, Everett J / Kirsch, David G / Saur, Dieter / Bazhin, Alexandr V / Trajkovic-Arsic, Marija / Heikenwalder, Mathias F / Siveke, Jens T. ·Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. · German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany. · Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina. · Medical Department, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians University, Munich, Germany. · German Caner Consortium (DKTK), Partner Site Munich, Germany. · Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany. · Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. j.siveke@dkfz.de. ·Cancer Res · Pubmed #29844119.

ABSTRACT: Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based

10 Article Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. 2018

Ruess, Dietrich A / Heynen, Guus J / Ciecielski, Katrin J / Ai, Jiaoyu / Berninger, Alexandra / Kabacaoglu, Derya / Görgülü, Kivanc / Dantes, Zahra / Wörmann, Sonja M / Diakopoulos, Kalliope N / Karpathaki, Angeliki F / Kowalska, Marlena / Kaya-Aksoy, Ezgi / Song, Liang / van der Laan, Eveline A Zeeuw / López-Alberca, María P / Nazaré, Marc / Reichert, Maximilian / Saur, Dieter / Erkan, Mert M / Hopt, Ulrich T / Sainz, Bruno / Birchmeier, Walter / Schmid, Roland M / Lesina, Marina / Algül, Hana. ·Mildred-Scheel-Chair of Tumor Metabolism, Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Surgery, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany. · Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany. · Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany. · Koç University School of Medicine, Istanbul, Turkey. · Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas "Alberto Sols", Madrid, Spain. · Mildred-Scheel-Chair of Tumor Metabolism, Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. hana.alguel@mri.tum.de. ·Nat Med · Pubmed #29808009.

ABSTRACT: The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors

11 Article Homoharringtonine could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells. 2018

Wang, Lele / Zhao, Linlin / Wei, Guo / Saur, Dieter / Seidler, Barbara / Wang, Junyan / Wang, Chuanxin / Qi, Tonggang. ·Central Research Laboratory, The Second Hospital of Shandong University, Jinan, China. · Department of Dermatology, The Second Hospital of Shandong University, Jinan, China. · The II. Medizinische Klinik und Poliklinik der Technischen Universität München, München, Germany. · Department of Internal Medicine, Dezhou People's Hospital, Dezhou, China. · The Third People's Hospital of Tibet, Central Laboratory, Lhasa, China. ·J Cell Biochem · Pubmed #29665121.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating disease with the 5-year survival rate less than 6%. In this study, we investigated if inhibiting protein synthesis directly with homoharringtonine (HHT) could induce acute apoptosis in pancreatic cancer cells through quick depletion of multiple short-lived critical members of the central proteome, example, PSMD11(26S proteasome non-ATPase regulatory subunit 11). It was shown that although HHT could inhibit proliferation and growth of MiaPaCa-2 and PANC-1 cells in a time- and dose-dependent manner, only part of pancreatic cancer cells could be induced to die through acute apoptosis. Mechanistic studies showed that HHT could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells. Inhibiting MEK1/ERK1/2 pathway with sorafenib could improve the cytotoxity of HHT in vitro and in a genetically engineered mouse model of pancreatic cancer. These results suggest that quick induction of PSMD11 or other acute apoptosis inhibitors through activation of the MEK1/ERK1/2 signaling pathway may be one of the important surviving mechanism which can help pancreatic cancer cells avoid acute apoptosis, it may have significant implications for the targeted therapy of pancreatic ductal adenocarcinoma.

12 Article MTOR inhibitor-based combination therapies for pancreatic cancer. 2018

Hassan, Zonera / Schneeweis, Christian / Wirth, Matthias / Veltkamp, Christian / Dantes, Zahra / Feuerecker, Benedikt / Ceyhan, Güralp O / Knauer, Shirley K / Weichert, Wilko / Schmid, Roland M / Stauber, Roland / Arlt, Alexander / Krämer, Oliver H / Rad, Roland / Reichert, Maximilian / Saur, Dieter / Schneider, Günter. ·Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany. · Institute of Pathology, Heinrich-Heine University and University Hospital Düsseldorf, 40225 Düsseldorf, Germany. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. · Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, 81675 München, Germany. · Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany. · Institute of Pathology, Technische Universität München, 81675 München, Germany. · Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Langenbeckstrasse 1, Mainz 55131, Germany. · Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz 55131, Germany. · Division of Gastroenterology and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ·Br J Cancer · Pubmed #29384525.

ABSTRACT: BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures. RESULTS: Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup. CONCLUSIONS: Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.

13 Article Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. 2018

Mueller, Sebastian / Engleitner, Thomas / Maresch, Roman / Zukowska, Magdalena / Lange, Sebastian / Kaltenbacher, Thorsten / Konukiewitz, Björn / Öllinger, Rupert / Zwiebel, Maximilian / Strong, Alex / Yen, Hsi-Yu / Banerjee, Ruby / Louzada, Sandra / Fu, Beiyuan / Seidler, Barbara / Götzfried, Juliana / Schuck, Kathleen / Hassan, Zonera / Arbeiter, Andreas / Schönhuber, Nina / Klein, Sabine / Veltkamp, Christian / Friedrich, Mathias / Rad, Lena / Barenboim, Maxim / Ziegenhain, Christoph / Hess, Julia / Dovey, Oliver M / Eser, Stefan / Parekh, Swati / Constantino-Casas, Fernando / de la Rosa, Jorge / Sierra, Marta I / Fraga, Mario / Mayerle, Julia / Klöppel, Günter / Cadiñanos, Juan / Liu, Pentao / Vassiliou, George / Weichert, Wilko / Steiger, Katja / Enard, Wolfgang / Schmid, Roland M / Yang, Fengtang / Unger, Kristian / Schneider, Günter / Varela, Ignacio / Bradley, Allan / Saur, Dieter / Rad, Roland. ·Center for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany. · Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. · Institute of Pathology, Technische Universität München, 81675 Munich, Germany. · The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK. · Comparative Experimental Pathology, Technische Universität München, 81675 Munich, Germany. · Anthropology & Human Genomics, Department of Biology II, Ludwig-Maximilians Universität, 82152 Martinsried, Germany. · Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany. · Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK. · Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), 33193 Oviedo, Spain. · Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain. · Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33011 Oviedo, Spain. · Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo, 33940 El Entrego, Spain. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, 81377 Munich, Germany. · Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC), 39012 Santander, Spain. ·Nature · Pubmed #29364867.

ABSTRACT: The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras

14 Article Diabetes as risk factor for pancreatic cancer: Hyperglycemia promotes epithelial-mesenchymal-transition and stem cell properties in pancreatic ductal epithelial cells. 2018

Rahn, Sascha / Zimmermann, Vivien / Viol, Fabrice / Knaack, Hendrike / Stemmer, Kerstin / Peters, Lena / Lenk, Lennart / Ungefroren, Hendrik / Saur, Dieter / Schäfer, Heiner / Helm, Ole / Sebens, Susanne. ·Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany. · Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany. · Department of General Surgery and Thoracic Surgery, UKSH Campus Kiel, Germany; First Department of Medicine, UKSH Campus Lübeck, Lübeck, Germany. · II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany. Electronic address: susanne.sebens@email.uni-kiel.de. ·Cancer Lett · Pubmed #29222037.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is associated with hyperglycemia and a risk to develop pancreatic ductal adenocarcinoma (PDAC), one of the most fatal malignancies. Cancer stem cells (CSC) are essential for initiation and maintenance of tumors, and acquisition of CSC-features is linked to epithelial-mesenchymal-transition (EMT). The present study investigated whether hyperglycemia promotes EMT and CSC-features in premalignant and malignant pancreatic ductal epithelial cells (PDEC). Under normoglycemia (5 mM d-glucose), Panc1 PDAC cells but not premalignant H6c7-kras cells exhibited a mesenchymal phenotype along with pronounced colony formation. While hyperglycemia (25 mM d-glucose) did not impact the mesenchymal phenotype of Panc1 cells, CSC-properties were aggravated exemplified by increased Nanog expression and Nanog-dependent formation of holo- and meroclones. In H6c7-kras cells, high glucose increased secretion of Transforming-Growth-Factor-beta1 (TGF-β1) as well as TGF-β1 signaling, and in a TGF-β1-dependent manner reduced E-cadherin expression, increased Nestin expression and number of meroclones. Finally, reduced E-cadherin expression was detected in pancreatic ducts of hyperglycemic but not normoglycemic mice. These data suggest that hyperglycemia promotes the acquisition of mesenchymal and CSC-properties in PDEC by activating TGF-β signaling and might explain how T2DM facilitates pancreatic tumorigenesis.

15 Article The hepatic microenvironment essentially determines tumor cell dormancy and metastatic outgrowth of pancreatic ductal adenocarcinoma. 2017

Lenk, Lennart / Pein, Maren / Will, Olga / Gomez, Beatriz / Viol, Fabrice / Hauser, Charlotte / Egberts, Jan-Hendrik / Gundlach, Jan-Paul / Helm, Ole / Tiwari, Sanjay / Weiskirchen, Ralf / Rose-John, Stefan / Röcken, Christoph / Mikulits, Wolfgang / Wenzel, Patrick / Schneider, Günter / Saur, Dieter / Schäfer, Heiner / Sebens, Susanne. ·Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany. · Cell Biology and Tumor Biology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany. · Molecular Imaging North Competence Center, Clinic of Radiology and Neuroradiology, CAU and UKSH Campus Kiel, Kiel, Germany. · Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, UKSH Campus Kiel, Kiel, Germany. · Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University, Aachen, Germany. · Department of Biochemistry, CAU, Kiel, Germany. · Institute of Pathology, UKSH Campus Kiel, Kiel, Germany. · Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. · II. Medizinische Klinik und Poliklinik, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. ·Oncoimmunology · Pubmed #29296518.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when liver metastases already emerged. This study elucidated the impact of hepatic stromal cells on growth behavior of premalignant and malignant pancreatic ductal epithelial cells (PDECs). Liver sections of tumor-bearing KPC mice comprised micrometastases displaying low proliferation located in an unobtrusive hepatic microenvironment whereas macrometastases containing more proliferating cells were surrounded by hepatic myofibroblasts (HMFs). In an age-related syngeneic PDAC mouse model livers with signs of age-related inflammation exhibited significantly more proliferating disseminated tumor cells (DTCs) and micrometastases despite comparable primary tumor growth and DTC numbers. Hepatic stellate cells (HSC), representing a physiologic liver stroma, promoted an IL-8 mediated quiescence-associated phenotype (QAP) of PDECs in coculture. QAP included flattened cell morphology, Ki67-negativity and reduced proliferation, elevated senescence-associated β galactosidase activity and diminished p-Erk/p-p38-ratio. In contrast, proliferation of PDECs was enhanced by VEGF in the presence of HMF. Switching the micromilieu from HSC to HMF or blocking VEGF reversed QAP in PDECs. This study demonstrates how HSCs induce and maintain a reversible QAP in disseminated PDAC cells, while inflammatory HMFs foster QAP reversal and metastatic outgrowth. Overall, the importance of the hepatic microenvironment in induction and reversal of dormancy during PDAC metastasis is emphasized.

16 Article HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. 2017

Stojanovic, N / Hassan, Z / Wirth, M / Wenzel, P / Beyer, M / Schäfer, C / Brand, P / Kroemer, A / Stauber, R H / Schmid, R M / Arlt, A / Sellmer, A / Mahboobi, S / Rad, R / Reichert, M / Saur, D / Krämer, O H / Schneider, G. ·II. Medizinische Klinik, Technische Universität München, München, Germany. · Department of Toxicology, University of Mainz Medical Center, Mainz, Germany. · Institute of Biochemistry and Biophysics/Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University Jena, Jena, Germany. · Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Mainz, Germany. · Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute of Pharmacy, Department of Pharmaceutical Chemistry I, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ·Oncogene · Pubmed #27721407.

ABSTRACT: Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.

17 Article In Vivo RNAi Screening for Pancreatic Cancer Drivers: PILOTing the WDR5-MYC Axis. 2016

Schneider, Günter / Saur, Dieter. ·Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675 München, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. ·Trends Cancer · Pubmed #28741490.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents a major global health problem that causes over 200000 deaths each year worldwide. The disease is highly resistant to cytotoxic and targeted therapies and the average survival is less than 12 months. This situation prompted Alessandro Carugo and Giulio Draetta to develop a novel genetic mouse system, termed Patient-Based In Vivo Lethality to Optimize Treatment (PILOT), to perform functional RNAi-based in vivo screens to uncover and target PDAC drivers. In a forward genetic screen focused on epigenetic modifiers, a WDR5-Myc axis that regulates the DNA replication checkpoint was identified and exploited in vivo for therapeutic intervention.

18 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.

19 Article siRNA-coupled nanoparticles for improved therapeutic targeting of pancreatic cancer. 2016

Lange, Sebastian / Saur, Dieter / Rad, Roland. ·Department of Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. ·Gut · Pubmed #27436269.

ABSTRACT: -- No abstract --

20 Article Novel small molecules targeting ciliary transport of Smoothened and oncogenic Hedgehog pathway activation. 2016

Jung, Bomi / Messias, Ana C / Schorpp, Kenji / Geerlof, Arie / Schneider, Günter / Saur, Dieter / Hadian, Kamyar / Sattler, Michael / Wanker, Erich E / Hasenöder, Stefan / Lickert, Heiko. ·Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Germany. · Institute of Stem Cell Research, Helmholtz Zentrum München, Germany. · Institute of Structural Biology, Helmholtz Zentrum München, Germany. · Center for Integrated Protein Science Munich at Biomolecular NMR Spectroscopy, Department Chemistry, Technische Universität München, 85747 Garching, Germany. · Assay Development and Screening Platform, Helmholtz Zentrum München, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar, München, Germany. · Technische Universität München, München, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · German Cancer Research Center (DKFZ), Heidelberg, Germany. · Neuroproteomics, Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany. · German Center for Diabetes Research (DZD), Germany. ·Sci Rep · Pubmed #26931153.

ABSTRACT: Trafficking of the G protein-coupled receptor (GPCR) Smoothened (Smo) to the primary cilium (PC) is a potential target to inhibit oncogenic Hh pathway activation in a large number of tumors. One drawback is the appearance of Smo mutations that resist drug treatment, which is a common reason for cancer treatment failure. Here, we undertook a high content screen with compounds in preclinical or clinical development and identified ten small molecules that prevent constitutive active mutant SmoM2 transport into PC for subsequent Hh pathway activation. Eight of the ten small molecules act through direct interference with the G protein-coupled receptor associated sorting protein 2 (Gprasp2)-SmoM2 ciliary targeting complex, whereas one antagonist of ionotropic receptors prevents intracellular trafficking of Smo to the PC. Together, these findings identify several compounds with the potential to treat drug-resistant SmoM2-driven cancer forms, but also reveal off-target effects of established drugs in the clinics.

21 Article Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice. 2016

Maresch, Roman / Mueller, Sebastian / Veltkamp, Christian / Öllinger, Rupert / Friedrich, Mathias / Heid, Irina / Steiger, Katja / Weber, Julia / Engleitner, Thomas / Barenboim, Maxim / Klein, Sabine / Louzada, Sandra / Banerjee, Ruby / Strong, Alexander / Stauber, Teresa / Gross, Nina / Geumann, Ulf / Lange, Sebastian / Ringelhan, Marc / Varela, Ignacio / Unger, Kristian / Yang, Fengtang / Schmid, Roland M / Vassiliou, George S / Braren, Rickmer / Schneider, Günter / Heikenwalder, Mathias / Bradley, Allan / Saur, Dieter / Rad, Roland. ·Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. · Institute of Radiology, Klinikum rechts der Isar, Technischen Universität München, 81675 Munich, Germany. · Department of Pathology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · Institute of Virology, Technische Universität München/Helmholtz Zentrum München, 81675 Munich, Germany. · Instituto de Biomedicina y Biotecnología de Cantabria, 39011 Santander, Spain. · Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ·Nat Commun · Pubmed #26916719.

ABSTRACT: Mouse transgenesis has provided fundamental insights into pancreatic cancer, but is limited by the long duration of allele/model generation. Here we show transfection-based multiplexed delivery of CRISPR/Cas9 to the pancreas of adult mice, allowing simultaneous editing of multiple gene sets in individual cells. We use the method to induce pancreatic cancer and exploit CRISPR/Cas9 mutational signatures for phylogenetic tracking of metastatic disease. Our results demonstrate that CRISPR/Cas9-multiplexing enables key applications, such as combinatorial gene-network analysis, in vivo synthetic lethality screening and chromosome engineering. Negative-selection screening in the pancreas using multiplexed-CRISPR/Cas9 confirms the vulnerability of pancreatic cells to Brca2-inactivation in a Kras-mutant context. We also demonstrate modelling of chromosomal deletions and targeted somatic engineering of inter-chromosomal translocations, offering multifaceted opportunities to study complex structural variation, a hallmark of pancreatic cancer. The low-frequency mosaic pattern of transfection-based CRISPR/Cas9 delivery faithfully recapitulates the stochastic nature of human tumorigenesis, supporting wide applicability for biological/preclinical research.

22 Article Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells. 2016

Diersch, S / Wirth, M / Schneeweis, C / Jörs, S / Geisler, F / Siveke, J T / Rad, R / Schmid, R M / Saur, D / Rustgi, A K / Reichert, M / Schneider, G. ·II. Medizinische Klinik, Technische Universität München, München, Germany. · Division of Translational Solid Tumor Oncology, German Cancer Consortium (DKTK), partner site Essen and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ·Oncogene · Pubmed #26592448.

ABSTRACT: Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D)-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras(G12D)-driven carcinogenesis in the pancreas.

23 Article A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer. 2015

Rad, Roland / Rad, Lena / Wang, Wei / Strong, Alexander / Ponstingl, Hannes / Bronner, Iraad F / Mayho, Matthew / Steiger, Katja / Weber, Julia / Hieber, Maren / Veltkamp, Christian / Eser, Stefan / Geumann, Ulf / Öllinger, Rupert / Zukowska, Magdalena / Barenboim, Maxim / Maresch, Roman / Cadiñanos, Juan / Friedrich, Mathias / Varela, Ignacio / Constantino-Casas, Fernando / Sarver, Aaron / Ten Hoeve, Jelle / Prosser, Haydn / Seidler, Barbara / Bauer, Judith / Heikenwälder, Mathias / Metzakopian, Emmanouil / Krug, Anne / Ehmer, Ursula / Schneider, Günter / Knösel, Thomas / Rümmele, Petra / Aust, Daniela / Grützmann, Robert / Pilarsky, Christian / Ning, Zemin / Wessels, Lodewyk / Schmid, Roland M / Quail, Michael A / Vassiliou, George / Esposito, Irene / Liu, Pentao / Saur, Dieter / Bradley, Allan. ·1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. [3] The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK. · The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK. · Department of Pathology, Klinikum Rechts der Isar, Technische Universität München, München, Germany. · 1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. [2] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, München, Germany. · Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain. · Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC-SODERCAN), Santander, Spain. · Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. · Biostatistics and Bioinformatics Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. · Bioinformatics and Statistics, The Netherlands Cancer Institute, Amsterdam, the Netherlands. · Institute of Virology, Technische Universität München, Munich, Germany. · Institute of Pathology, Ludwig Maximilians Universität München, München, Germany. · Institute of Pathology, Universität Regensburg, Regensburg, Germany. · Institute of Pathology, Technische Universität Dresden, Dresden, Germany. · Department of Surgery, Technische Universität Dresden, Dresden, Germany. · Institute of Pathology, Medizinische Universität Insbruck, Insbruck, Austria. ·Nat Genet · Pubmed #25485836.

ABSTRACT: Here we describe a conditional piggyBac transposition system in mice and report the discovery of large sets of new cancer genes through a pancreatic insertional mutagenesis screen. We identify Foxp1 as an oncogenic transcription factor that drives pancreatic cancer invasion and spread in a mouse model and correlates with lymph node metastasis in human patients with pancreatic cancer. The propensity of piggyBac for open chromatin also enabled genome-wide screening for cancer-relevant noncoding DNA, which pinpointed a Cdkn2a cis-regulatory region. Histologically, we observed different tumor subentities and discovered associated genetic events, including Fign insertions in hepatoid pancreatic cancer. Our studies demonstrate the power of genetic screening to discover cancer drivers that are difficult to identify by other approaches to cancer genome analysis, such as downstream targets of commonly mutated human cancer genes. These piggyBac resources are universally applicable in any tissue context and provide unique experimental access to the genetic complexity of cancer.

24 Article Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α. 2014

Baer, Romain / Cintas, Célia / Dufresne, Marlène / Cassant-Sourdy, Stéphanie / Schönhuber, Nina / Planque, Laetitia / Lulka, Hubert / Couderc, Bettina / Bousquet, Corinne / Garmy-Susini, Barbara / Vanhaesebroeck, Bart / Pyronnet, Stéphane / Saur, Dieter / Guillermet-Guibert, Julie. ·UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France; · UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; · Department of Internal Medicine 2, Technische Universität München, 81675 Munich, Germany; · UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Inserm, F-31000 Toulouse, France; Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; · Cell Signaling, UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom; · Department of Internal Medicine 2, Technische Universität München, 81675 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ·Genes Dev · Pubmed #25452273.

ABSTRACT: Increased PI 3-kinase (PI3K) signaling in pancreatic ductal adenocarcinoma (PDAC) correlates with poor prognosis, but the role of class I PI3K isoforms during its induction remains unclear. Using genetically engineered mice and pharmacological isoform-selective inhibitors, we found that the p110α PI3K isoform is a major signaling enzyme for PDAC development induced by a combination of genetic and nongenetic factors. Inactivation of this single isoform blocked the irreversible transition of exocrine acinar cells into pancreatic preneoplastic ductal lesions by oncogenic Kras and/or pancreatic injury. Hitting the other ubiquitous isoform, p110β, did not prevent preneoplastic lesion initiation. p110α signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110α was necessary for pancreatic ductal cancers to arise from Kras-induced preneoplastic lesions by increasing epithelial cell proliferation in the context of mutated p53. Here we identify an in vivo context in which p110α cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110α is required for PDAC induced by oncogenic Kras, the key driver mutation of PDAC. These data are critical for a better understanding of the development of this lethal disease that is currently without efficient treatment.

25 Article A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. 2014

Schönhuber, Nina / Seidler, Barbara / Schuck, Kathleen / Veltkamp, Christian / Schachtler, Christina / Zukowska, Magdalena / Eser, Stefan / Feyerabend, Thorsten B / Paul, Mariel C / Eser, Philipp / Klein, Sabine / Lowy, Andrew M / Banerjee, Ruby / Yang, Fangtang / Lee, Chang-Lung / Moding, Everett J / Kirsch, David G / Scheideler, Angelika / Alessi, Dario R / Varela, Ignacio / Bradley, Allan / Kind, Alexander / Schnieke, Angelika E / Rodewald, Hans-Reimer / Rad, Roland / Schmid, Roland M / Schneider, Günter / Saur, Dieter. ·Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany. · German Cancer Research Center (DKFZ), Division for Cellular Immunology, Heidelberg, Germany. · Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, München, Germany. · Moores Cancer Center, Division of Surgical Oncology, University of California San Diego, La Jolla, California, USA. · Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, UK. · Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA. · Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA. · Helmholtz Zentrum München, Research Unit Comparative Medicine, Neuherberg, Germany. · MRC Protein Phosphorylation Unit, University of Dundee, Dundee, UK. · Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain. · Livestock Biotechnology, Technische Universität München, Freising, Germany. · German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. ·Nat Med · Pubmed #25326799.

ABSTRACT: Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP-based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell-autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.

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