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Pancreatic Neoplasms: HELP
Articles by Philipp Bruns
Based on 7 articles published since 2010
(Why 7 articles?)
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Between 2010 and 2020, Philipp Bruns wrote the following 7 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis. 2019

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

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

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

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

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

3 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.

4 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.

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

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

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

6 Article A novel NHE1-centered signaling cassette drives epidermal growth factor receptor-dependent pancreatic tumor metastasis and is a target for combination therapy. 2015

Cardone, Rosa Angela / Greco, Maria Raffaella / Zeeberg, Katrine / Zaccagnino, Angela / Saccomano, Mara / Bellizzi, Antonia / Bruns, Philipp / Menga, Marta / Pilarsky, Christian / Schwab, Albrecht / Alves, Frauke / Kalthoff, Holger / Casavola, Valeria / Reshkin, Stephan Joel. ·Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy. · Institute for Experimental Cancer Research, Christian Albrechts University, Arnold-Heller-Str. 7, D-24105, Kiel, Germany. · Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, D-37075, Gottingen, Germany. · Institute of Physiology II, University of Muenster, Robert-Koch-Str. 27 b, D-48149, Muenster, Germany. · University Hospital Carl Gustav Carus, Technical University of Dresden, TU Dresden, Fetscherstraße 74, D-01307, Dresden, Germany. · Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy; Centre of Excellence in Comparative Genomics (CEGBA), Bari, Italy. · Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70125, Bari, Italy; Centre of Excellence in Comparative Genomics (CEGBA), Bari, Italy. Electronic address: stephanjoel.reshkin@uniba.it. ·Neoplasia · Pubmed #25748234.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR) is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na(+)/H(+) exchanger (NHE1) associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na+/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na+/H+ exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib.

7 Article Complexity of molecular alterations impacts pancreatic cancer prognosis. 2013

Regel, Ivonne / Kong, Bo / Bruns, Philipp / Michalski, Christoph W / Kleeff, Jörg. ·Ivonne Regel, Bo Kong, Philipp Bruns, Christoph W Michalski, Jörg Kleeff, Department of Surgery, Technische Universität München, 81675 München, Germany. ·World J Gastrointest Oncol · Pubmed #23355925.

ABSTRACT: Individualized cancer treatment (e.g. targeted therapy) based on molecular alterations has emerged as an important strategy to improve the current standard-of-care chemotherapy. A large number of studies have demonstrated the importance of biomarkers not only in predicting prognosis but more importantly in predicting the response towards therapies. For example, amplification or mutation status of the two biomarkers HER2 (human epidermal growth factor 2) and BRCA (breast cancer) can be used to decide on a specific targeted therapy in breast cancer. However, no biomarkers with a similar clinical impact have been identified in pancreatic ductal adenocarcinoma. Although many genome-wide and proteome-based high-throughput studies have identified candidate genes or proteins as promising biomarkers, none of them were eventually transferred into the clinical setting. Notably, the most reliable markers for predicting prognosis are still the tumor stage and grade and biomarkers for therapy response remain undefined. One reason lies in the lack of systemic approaches to analyze the complexity of dominating cancer pathways and the impact of such signal complexity on prognosis and therapy response.