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Pancreatic Neoplasms: HELP
Articles by Roland Rad
Based on 12 articles published since 2009
(Why 12 articles?)
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Between 2009 and 2019, R. Rad wrote the following 12 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma. 2018

Mahajan, Ujjwal Mukund / Langhoff, Eno / Goni, Elisabetta / Costello, Eithne / Greenhalf, William / Halloran, Christopher / Ormanns, Steffen / Kruger, Stephan / Boeck, Stefan / Ribback, Silvia / Beyer, Georg / Dombroswki, Frank / Weiss, Frank-Ulrich / Neoptolemos, John P / Werner, Jens / D'Haese, Jan G / Bazhin, Alexandr / Peterhansl, Julian / Pichlmeier, Svenja / Büchler, Markus W / Kleeff, Jörg / Ganeh, Paula / Sendler, Matthias / Palmer, Daniel H / Kohlmann, Thomas / Rad, Roland / Regel, Ivonne / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Germany. · Department of Pathology, University Medicine Greifswald, Greifswald, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, Halle, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. ·Gastroenterology · Pubmed #30092175.

ABSTRACT: BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

2 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.

3 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

4 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.

5 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 --

6 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.

7 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.

8 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.

9 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.

10 Article Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. 2013

Eser, Stefan / Reiff, Nina / Messer, Marlena / Seidler, Barbara / Gottschalk, Kathleen / Dobler, Melanie / Hieber, Maren / Arbeiter, Andreas / Klein, Sabine / Kong, Bo / Michalski, Christoph W / Schlitter, Anna Melissa / Esposito, Irene / Kind, Alexander J / Rad, Lena / Schnieke, Angelika E / Baccarini, Manuela / Alessi, Dario R / Rad, Roland / Schmid, Roland M / Schneider, Günter / Saur, Dieter. ·Department of Internal Medicine 2, Technische Universität München, Ismaningerstr. 22, 81675 München, Germany. ·Cancer Cell · Pubmed #23453624.

ABSTRACT: Oncogenic Kras activates a plethora of signaling pathways, but our understanding of critical Ras effectors is still very limited. We show that cell-autonomous phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1), but not Craf, are key effectors of oncogenic Kras in the pancreas, mediating cell plasticity, acinar-to-ductal metaplasia (ADM), and pancreatic ductal adenocarcinoma (PDAC) formation. This contrasts with Kras-driven non-small cell lung cancer, where signaling via Craf, but not PDK1, is an essential tumor-initiating event. These in vivo genetic studies together with pharmacologic treatment studies in models of human ADM and PDAC demonstrate tissue-specific differences of oncogenic Kras signaling and define PI3K/PDK1 as a suitable target for therapeutic intervention specifically in PDAC.

11 Article Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. 2010

Mazur, Pawel K / Einwächter, Henrik / Lee, Marcel / Sipos, Bence / Nakhai, Hassan / Rad, Roland / Zimber-Strobl, Ursula / Strobl, Lothar J / Radtke, Freddy / Klöppel, Günter / Schmid, Roland M / Siveke, Jens T. ·Second Department of Internal Medicine and Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. ·Proc Natl Acad Sci U S A · Pubmed #20624967.

ABSTRACT: Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic intraepithelial neoplasia (PanIN) lesions. Using genetically engineered mice, we demonstrate the effect of conditional Notch receptor ablation in KrasG12D-driven pancreatic carcinogenesis. Deficiency of Notch2 but not Notch1 stops PanIN progression, prolongs survival, and leads to a phenotypical switch toward anaplastic pancreatic cancer with epithelial-mesenchymal transition. By expression profiling, we identified increased Myc signaling regulated by Notch2 during tumor development, placing Notch2 as a central regulator of PanIN progression and malignant transformation. Our study supports the concept of distinctive roles of individual Notch receptors in cancer development.

12 Article Interleukin 1 beta gene promoter SNPs are associated with risk of pancreatic cancer. 2009

Hamacher, Rainer / Diersch, Sandra / Scheibel, Melanie / Eckel, Florian / Mayr, Martina / Rad, Roland / Bajbouj, Monther / Schmid, Roland M / Saur, Dieter / Schneider, Günter. ·Technische Universität of München, II. Medizinische Klinik, Klinikum rechts der Isar, Ismaninger Str. 22, 81675 Munich, Germany. ·Cytokine · Pubmed #19251436.

ABSTRACT: Epidemiological and experimental data demonstrate, that inflammation contributes significantly to pancreatic carcinogenesis. IL1beta, a pleiotropic cytokine produced by inflammatory cells and tumor cells, promotes cancer progression. Single nucleotide polymorphisms (SNPs) of the IL1beta promoter were found to be associated with an increased risk for certain cancers. In this case-control study we determined IL1beta promoter SNPs in 73 patients with pancreatic cancer and 235 controls. We found that the IL1beta -511CT/-31TC genotype was significantly associated with an increased risk for pancreatic cancer (OR 1.42, p=0.0456). Among pancreatic cancer cases, patients with the -511CT/-31TC genotype had less frequently resectable disease than patients with other IL1beta -511/-31 genotypes (p=0.0323). Furthermore, the IL1beta -511CT/-31TC genotype was more frequent observed in UICC stage IV (p=0.039) and undifferentiated tumors (G3) (p=0.019). In addition, we found that the proinflammatory IL1beta -511CT/-31TC alleles define an IL1beta secretory phenotype in pancreatic cancer cell lines in vitro. These findings provide a first evidence for an association of the IL1beta gene promoter SNPs with risk for pancreatic cancer.