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Pancreatic Neoplasms: HELP
Articles by Johannes Beckers
Based on 2 articles published since 2010
(Why 2 articles?)
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Between 2010 and 2020, Johannes Beckers wrote the following 2 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy. 2018

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

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

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

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

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