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Pancreatic Neoplasms: HELP
Articles by Robert Häsler
Based on 4 articles published since 2010
(Why 4 articles?)
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Between 2010 and 2020, R. Häsler wrote the following 4 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 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.

2 Article Role of CCL20 mediated immune cell recruitment in NF-κB mediated TRAIL resistance of pancreatic cancer. 2017

Geismann, Claudia / Grohmann, Frauke / Dreher, Anita / Häsler, Robert / Rosenstiel, Philip / Legler, Karen / Hauser, Charlotte / Egberts, Jan Hendrik / Sipos, Bence / Schreiber, Stefan / Linkermann, Andreas / Hassan, Zonera / Schneider, Günter / Schäfer, Heiner / Arlt, Alexander. ·Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany. · Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, UKSH Campus Kiel, Kiel, Germany. · Department of Surgery, UKSH Campus Kiel, Kiel, German. · Institute of Pathology, University Hospital Tübingen, Tübingen, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Clinical Molecular Biology, UKSH Campus Kiel, Germany. · Clinic for Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany. · Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany; Institute of Experimental Cancer Research, UKSH Campus Kiel, Germany. · Department of Internal Medicine I, Laboratory of Molecular Gastroenterology & Hepatology, UKSH-Campus Kiel, Kiel, Germany. Electronic address: aarlt@1med.uni-kiel.de. ·Biochim Biophys Acta Mol Cell Res · Pubmed #28188806.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers. From a clinical view, the transcription factor NF-κB is of particular importance, since this pathway confers apoptosis resistance and limits drug efficacy. Whereas the role of the most abundant NF-κB subunit p65/RelA in therapeutic resistance is well documented, only little knowledge of the RelA downstream targets and their functional relevance in TRAIL mediated apoptosis in PDAC is available. In the present study TRAIL resistant and sensitive PDAC cell lines were analyzed for differentially expressed RelA target genes, to define RelA downstream targets mediating TRAIL resistance. The most upregulated target gene was then further functionally characterized. Unbiased genome-wide expression analysis demonstrated that the chemokine CCL20 represents the strongest TRAIL inducible direct RelA target gene in resistant PDAC cells. Unexpectedly, targeting CCL20 by siRNA, blocking antibodies or by downregulation of the sole CCL20 receptor CCR6 had no effect on PDAC cell death or cancer cell migration, arguing against an autocrine role of CCL20 in PDAC. However, by using an ex vivo indirect co-culture system we were able to show that CCL20 acts paracrine to recruit immune cells. Importantly, CCL20-recruited immune cells further increase TRAIL resistance of CCL20-producing PDAC cells. In conclusion, our data show a functional role of a RelA-CCL20 pathway in PDAC TRAIL resistance. We demonstrate how the therapy-induced cross-talk of cancer cells with immune cells affects treatment responses, knowledge needed to tailor novel bi-specific treatments, which target tumor cell as well as immune cells.

3 Article c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells. 2014

Geismann, C / Grohmann, F / Sebens, S / Wirths, G / Dreher, A / Häsler, R / Rosenstiel, P / Hauser, C / Egberts, J-H / Trauzold, A / Schneider, G / Sipos, B / Zeissig, S / Schreiber, S / Schäfer, H / Arlt, A. ·Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. · Institute for Experimental Medicine, Kiel, Germany. · Institute of Clinical Molecular Biology, Kiel, Germany. · Department of Surgery, Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, Kiel, Germany. · Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Munich, Germany. · Institute of Pathology, University Hospital Tübingen, Tübingen, Germany. · 1] Laboratory of Molecular Gastroenterology and Hepatology, 1st Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany [2] Institute of Clinical Molecular Biology, Kiel, Germany. ·Cell Death Dis · Pubmed #25299780.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF-κB signalling has been shown to be critical for this profound cell-autonomous resistance against chemotherapeutic drugs and death receptor-induced apoptosis, but little is known about the role of the c-Rel subunit in solid cancer and PDAC apoptosis control. In the present study, by analysis of genome-wide patterns of c-Rel-dependent gene expression, we were able to establish c-Rel as a critical regulator of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in PDAC. TRAIL-resistant cells exhibited a strong TRAIL-inducible NF-κB activity, whereas TRAIL-sensitive cells displayed only a small increase in NF-κB-binding activity. Transfection with siRNA against c-Rel sensitized the TRAIL-resistant cells in a manner comparable to siRNA targeting the p65/RelA subunit. Gel-shift analysis revealed that c-Rel is part of the TRAIL-inducible NF-κB complex in PDAC. Array analysis identified NFATc2 as a c-Rel target gene among the 12 strongest TRAIL-inducible genes in apoptosis-resistant cells. In line, siRNA targeting c-Rel strongly reduced TRAIL-induced NFATc2 activity in TRAIL-resistant PDAC cells. Furthermore, siRNA targeting NFATc2 sensitized these PDAC cells against TRAIL-induced apoptosis. Finally, TRAIL-induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacologic inhibition of COX-2 with celecoxib or siRNA targeting COX-2, enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel-, NFATc2- and COX-2-dependent antiapoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.

4 Article Nuclear death receptor TRAIL-R2 inhibits maturation of let-7 and promotes proliferation of pancreatic and other tumor cells. 2014

Haselmann, Verena / Kurz, Alexandra / Bertsch, Uwe / Hübner, Sebastian / Olempska-Müller, Monika / Fritsch, Jürgen / Häsler, Robert / Pickl, Andreas / Fritsche, Hendrik / Annewanter, Franka / Engler, Christine / Fleig, Barbara / Bernt, Alexander / Röder, Christian / Schmidt, Hendrik / Gelhaus, Christoph / Hauser, Charlotte / Egberts, Jan-Hendrik / Heneweer, Carola / Rohde, Anna Maria / Böger, Christine / Knippschild, Uwe / Röcken, Christoph / Adam, Dieter / Walczak, Henning / Schütze, Stefan / Janssen, Ottmar / Wulczyn, F Gregory / Wajant, Harald / Kalthoff, Holger / Trauzold, Anna. ·Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany. · Institute of Immunology, University of Kiel, Kiel, Germany. · Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany. · Zoological Institute, University of Kiel, Kiel, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany; Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University of Kiel, Kiel, Germany. · Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University of Kiel, Kiel, Germany. · Clinic for Diagnostic Radiology, University of Kiel, Kiel, Germany. · Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. · Institute of Pathology, University of Kiel, Kiel, Germany. · Department of General, Visceral and Transplantation Surgery, Centre of Surgery, University of Ulm, Ulm, Germany. · Centre for Cell Death, Cancer and Inflammation, University College London Cancer Institute, London, United Kingdom. · Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany. · Division of Molecular Oncology, Institute for Experimental Cancer Research, University of Kiel, Kiel, Germany. Electronic address: atrauzold@email.uni-kiel.de. ·Gastroenterology · Pubmed #24120475.

ABSTRACT: BACKGROUND & AIMS: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL-R1) (TNFRSF10A) and TRAIL-R2 (TNFRSF10B) on the plasma membrane bind ligands that activate apoptotic and other signaling pathways. Cancer cells also might have TRAIL-R2 in the cytoplasm or nucleus, although little is known about its activities in these locations. We investigated the functions of nuclear TRAIL-R2 in cancer cell lines. METHODS: Proteins that interact with TRAIL-R2 initially were identified in pancreatic cancer cells by immunoprecipitation, mass spectrometry, and immunofluorescence analyses. Findings were validated in colon, renal, lung, and breast cancer cells. Functions of TRAIL-R2 were determined from small interfering RNA knockdown, real-time polymerase chain reaction, Drosha-activity, microRNA array, proliferation, differentiation, and immunoblot experiments. We assessed the effects of TRAIL-R2 overexpression or knockdown in human pancreatic ductal adenocarcinoma (PDAC) cells and their ability to form tumors in mice. We also analyzed levels of TRAIL-R2 in sections of PDACs and non-neoplastic peritumoral ducts from patients. RESULTS: TRAIL-R2 was found to interact with the core microprocessor components Drosha and DGCR8 and the associated regulatory proteins p68, hnRNPA1, NF45, and NF90 in nuclei of PDAC and other tumor cells. Knockdown of TRAIL-R2 increased Drosha-mediated processing of the let-7 microRNA precursor primary let-7 (resulting in increased levels of mature let-7), reduced levels of the let-7 targets (LIN28B and HMGA2), and inhibited cell proliferation. PDAC tissues from patients had higher levels of nuclear TRAIL-R2 than non-neoplastic pancreatic tissue, which correlated with increased nuclear levels of HMGA2 and poor outcomes. Knockdown of TRAIL-R2 in PDAC cells slowed their growth as orthotopic tumors in mice. Reduced nuclear levels of TRAIL-R2 in cultured pancreatic epithelial cells promoted their differentiation. CONCLUSIONS: Nuclear TRAIL-R2 inhibits maturation of the microRNA let-7 in pancreatic cancer cell lines and increases their proliferation. Pancreatic tumor samples have increased levels of nuclear TRAIL-R2, which correlate with poor outcome of patients. These findings indicate that in the nucleus, death receptors can function as tumor promoters and might be therapeutic targets.