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Pancreatic Neoplasms: HELP
Articles by Mathias F. Heikenwalder
Based on 6 articles published since 2010
(Why 6 articles?)
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Between 2010 and 2020, Mathias Heikenwalder wrote the following 6 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 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

2 Article Pancreatic Premalignant Lesions Secrete Tissue Inhibitor of Metalloproteinases-1, Which Activates Hepatic Stellate Cells Via CD63 Signaling to Create a Premetastatic Niche in the Liver. 2016

Grünwald, Barbara / Harant, Veronika / Schaten, Susanne / Frühschütz, Monika / Spallek, Ria / Höchst, Bastian / Stutzer, Katharina / Berchtold, Sonja / Erkan, Mert / Prokopchuk, Olga / Martignoni, Marc / Esposito, Irene / Heikenwalder, Mathias / Gupta, Aayush / Siveke, Jens / Saftig, Paul / Knolle, Percy / Wohlleber, Dirk / Krüger, Achim. ·Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany. · Chirurgische Klinik Technische Universität München, München, Germany. · Institut für Pathologie, Klinikum rechts der Isar, Technische Universität München, München, Germany. · Institut für Virologie, Technische Universität München, München, Germany. · II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany. · Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany. · Institut für Molekulare Immunologie und Experimentelle Onkologie, Technische Universität München, München, Germany. Electronic address: achim.krueger@tum.de. ·Gastroenterology · Pubmed #27506299.

ABSTRACT: BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) metastasizes to liver at early stages, making this disease highly lethal. Tissue inhibitor of metalloproteinases-1 (TIMP1) creates a metastasis-susceptible environment in the liver. We investigated the role of TIMP1 and its receptor CD63 in metastasis of early-stage pancreatic tumors using mice and human cell lines and tissue samples. METHODS: We obtained liver and plasma samples from patients in Germany with chronic pancreatitis, pancreatic intra-epithelial neoplasia, or PDAC, as well as hepatic stellate cells (HSCs). We performed studies with Ptf1a RESULTS: Chronic pancreatitis, pancreatic intra-epithelial neoplasia, and PDAC tissues from patients expressed higher levels of TIMP1 protein than normal pancreas. The premalignant pancreatic lesions that developed in KPC and CPK mice expressed TIMP1 and secreted it into the circulation. In vitro and in vivo, TIMP1 activated human or mouse HSCs, which required interaction between TIMP1 and CD63 and signaling via phosphatidylinositol 3-kinase, but not TIMP1 protease inhibitor activity. This signaling pathway induced expression of endogenous TIMP1. TIMP1 knockdown in HSCs reduced their activation. Cultured TIMP1-activated human and mouse HSCs began to express stromal-derived factor-1, which induced neutrophil migration, a marker of the premetastatic niche. Mice with pancreatic intra-epithelial neoplasia-derived systemic increases in TIMP1 developed more liver metastases after injections of pancreatic cancer cells than mice without increased levels of TIMP1. This increase in formation of liver metastases from injected pancreatic cancer cells was not observed in TIMP1 or CD63 knockout mice. CONCLUSIONS: Expression of TIMP1 is increased in chronic pancreatitis, pancreatic intra-epithelial neoplasia, and PDAC tissues from patients. TIMP1 signaling via CD63 leads to activation of HSCs, which create an environment in the liver that increases its susceptibility to pancreatic tumor cells. Strategies to block TIMP1 signaling via CD63 might be developed to prevent PDAC metastasis to the liver.

3 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.

4 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.

5 Article Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. 2015

Mazur, Pawel K / Herner, Alexander / Mello, Stephano S / Wirth, Matthias / Hausmann, Simone / Sánchez-Rivera, Francisco J / Lofgren, Shane M / Kuschma, Timo / Hahn, Stephan A / Vangala, Deepak / Trajkovic-Arsic, Marija / Gupta, Aayush / Heid, Irina / Noël, Peter B / Braren, Rickmer / Erkan, Mert / Kleeff, Jörg / Sipos, Bence / Sayles, Leanne C / Heikenwalder, Mathias / Heßmann, Elisabeth / Ellenrieder, Volker / Esposito, Irene / Jacks, Tyler / Bradner, James E / Khatri, Purvesh / Sweet-Cordero, E Alejandro / Attardi, Laura D / Schmid, Roland M / Schneider, Guenter / Sage, Julien / Siveke, Jens T. ·Department of Pediatrics, Stanford University School of Medicine, California, USA. · Department of Genetics, Stanford University School of Medicine, California, USA. · Second Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Radiation Oncology, Stanford University School of Medicine, California, USA. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · David H. Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. · Department of Medicine, Stanford University School of Medicine, California, USA. · Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, California, USA. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Ruhr-University Bochum, Medical Clinic, Knappschaftskrankenhaus, Bochum, Germany. · Institute of Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Pathology, University of Tübingen, Tübingen, Germany. · Institute of Virology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research center (DKFZ) Heidelberg, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. · Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. · German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. ·Nat Med · Pubmed #26390243.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.

6 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.