T Seufferlein

Philipps University of Marburg, Marburg, Hesse, Germany

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Publications (275)992.53 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypersecretion is the major symptom of functional neuroendocrine tumours. The mechanisms that contribute to this excessive secretion of hormones are still elusive. A key event in secretion is the exit of secretory products from the Golgi apparatus. ADP-ribosylation factor (Arf) GTPases are known to control vesicle budding and trafficking, and have a leading function in the regulation of formation of secretory granula at the Golgi. Here, we show that Arf1 is the predominant Arf protein family member expressed in the neuroendocrine pancreatic tumour cell lines BON and QGP-1. In BON cells Arf1 colocalizes with Golgi markers as well as chromogranin A, and shows significant basal activity. The inhibition of Arf1 activity or expression significantly impaired secretion of chromogranin A. Furthermore, we show that the insulin-like growth factor 1 (IGF-1), a major regulator of growth and secretion in BON cells, induces Arf1 activity. We found that activation of Arf1 upon IGF-1 receptor stimulation is mediated by MEK/ERK signalling pathway in BON and QGP-1 cells. Moreover, the activity of Arf1 in BON cells is mediated by autocrinely secreted IGF-1, and concomitantly, autocrine IGF1 secretion is maintained by Arf1 activity. In summary, our data indicate an important regulatory role for Arf1 at the Golgi in hypersecretion in neuroendocrine cancer cells. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
    Journal of Cellular and Molecular Medicine 02/2015; DOI:10.1111/jcmm.12473 · 3.70 Impact Factor
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    ABSTRACT: Microenvironmental clues are critical to cell behavior. One of the key elements of migration is the generation and response to forces. Up to now there is no definitive concept on how the generation and responses to cellular forces influence cell behavior. Here we show that phosphorylation of paxillin is a crucial event in the response to exogenous forces. Application of force induced growth of adhesion sites and this phenomenon was accompanied by a downregulation of Src family kinase activity, which in turn led to a decrease in the phosphorylation of paxillin at the tyrosine residues Y31 and Y118. The force-dependent growth of adhesion sites is mediated by a decrease in the turnover-rate of paxillin in focal contacts. This turnover critically depended on the phosphorylation state of paxiilin at Y31/118. Paxillin is an important regulator in the control of the aggregate state of the whole adhesion site since the turnover of other adhesion site proteins such as vinculin is influenced by the phosphorylation state of paxillin as well. Taken together these data suggest that SFK dependent phosphorylation of paxillin is a crucial event in the regulation of adhesion site function in response to force. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Cytoskeleton 01/2015; DOI:10.1002/cm.21209 · 3.01 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2015; 53(01). DOI:10.1055/s-0034-1397045 · 1.67 Impact Factor
  • 01/2015; DOI:10.4161/23723556.2014.981444
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    ABSTRACT: The kinase PRKD2 is a crucial regulator of tumor cell-endothelial cell communication in gastrointestinal tumors and glioblastomas, but its mechanistic contributions to malignant development are not understood. Here we report that the oncogenic chaperone HSP90 binds to and stabilizes PRKD2 in human cancer cells. Pharmacologic inhibition of HSP90 with structurally divergent small molecules currently in clinical development triggered proteasome-dependent degradation of PRKD2, augmenting apoptosis in human cancer cells of various tissue origins. Conversely, ectopic expression of PRKD2 protected cancer cells from the apoptotic effects of HSP90 abrogation, restoring blood vessel formation in two preclinical models of solid tumors. Mechanistic studies revealed that PRKD2 is essential for hypoxia-induced accumulation of HIF-1α and activation of NF-κB in tumor cells. Notably, ectopic expression PRKD2 was able to partially restore HIF-1α and secreted VEGF-A levels in hypoxic cancer cells treated with HSP90 inhibitors. Taken together, our findings indicate that signals from hypoxia and HSP90 pathways are interconnected and funneled by PRKD2 into the NF-κB/ VEGF-A signaling axis to promote tumor angiogenesis and tumor growth.
    Cancer Research 10/2014; 74(23). DOI:10.1158/0008-5472.CAN-14-1017 · 9.28 Impact Factor
  • A Illing, M Hohwieler, T Seufferlein, A Kleger
    Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386070 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386212 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386203 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386103 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386080 · 1.67 Impact Factor
  • R Sroka, T Eiseler, T Seufferlein
    Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386047 · 1.67 Impact Factor
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    ABSTRACT: Pancreatic adenocarcinomas are associated with a poor survival prognosis. Besides curative surgical resection, only limited therapies with modest impact are available. New evidence suggests that the mammalian target of rapamycin pathway may be involved in the pathogenesis of neuroendocrine tumors, and breast and renal cell cancer. The phase I study described here was therefore designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating doses of the mammalian target of rapamycin inhibitor everolimus in combination with gemcitabine in patients with advanced pancreatic cancer. Eligible patients had histologically confirmed locally advanced and/or metastatic pancreatic carcinoma and were administered 5 mg everolimus every second day (cohort 1, 2, 3) or 5 mg daily (cohort 4, 5) in combination with escalating low-dose gemcitabine. It was found that if two patients showed DLTs, MTD was reached and gemcitabine dose escalation was stopped at this level. Twenty-seven patients were enrolled in the study (cohort 1: n=3; cohort 2: n=4; cohort 3: n=6; cohort 4: n=7; cohort 5: n=7) and received a maximum 600 mg gemcitabine/week. In cohort 5, two of the six patients experienced DLTs (grade 3 liver toxicity lasting for>7 days). MTD was measured as 400 mg/m/week gemcitabine plus 5 mg/day everolimus. The MTD of a low-dose gemcitabine treatment in combination with everolimus was determined and no new safety concerns were identified in patients with advanced pancreatic cancer.
    Anti-Cancer Drugs 07/2014; 25(9). DOI:10.1097/CAD.0000000000000146 · 1.89 Impact Factor
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    ABSTRACT: Background Gemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers. Methods In this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) with or without cetuximab (500 mg/m2), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00552149. Findings Between Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52–74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43–65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1–7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7–6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1–13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6–16·0) in the chemotherapy alone group. The most common grade 3–4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of atypical pneumonia related to treatment in the chemotherapy alone group. Interpretation The addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with advanced biliary cancer, although it was well tolerated. Gemcitabine and platinum-based combination should remain the standard treatment option. Funding Institut National du Cancer, Merck Serono.
    The Lancet Oncology 07/2014; 15(8). DOI:10.1016/S1470-2045(14)70212-8 · 24.73 Impact Factor
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    ABSTRACT: Ductal adenocarcinoma of the pancreas is the fourth most common cause of death from cancer in men and women in Germany: about 15 000 persons die of this disease each year.
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    ABSTRACT: Epidermal growth factor receptor inhibitor (EGFRI) induced skin toxicity has a prognostic value suggesting skin toxicity can be a useful surrogate marker for successful epidermal growth factor receptor (EGFR) inhibition, improved response and survival. But the pathophysiology of EGFRI induced skin toxicity remains elusive. However the involvement of immunological mechanisms has been speculated. This study investigates the possible underlying mechanism of EGFR inhibition associated cytokine production in keratinocytes as well as in patients after treatment with epidermal growth factor receptor inhibitors (EGFRIs).
    European journal of cancer (Oxford, England: 1990) 05/2014; 50(11). DOI:10.1016/j.ejca.2014.04.026 · 4.12 Impact Factor
  • Christoph Wille, Thomas Seufferlein, Tim Eiseler
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    ABSTRACT: Highly invasive pancreatic tumors are often recognized in late stages due to a lack of clear symptoms and pose major challenges for treatment and disease management. Broad-band Protein Kinase D (PKD) inhibitors have recently been proposed as additional treatment option for this disease. PKDs are implicated in the control of cancer cell motility, angiogenesis, proliferation and metastasis. In particular, PKD2 expression is elevated in pancreatic cancer, whereas PKD1 expression is comparably lower. In our recent study we report that both kinases control PDAC cell invasive properties in an isoform-specific, but opposing manner. PKD1 selectively mediates anti-migratory/anti-invasive features by preferential regulation of the actin-regulatory Cofilin-phosphatase Slingshot1L (SSH1L). PKD2, on the other hand enhances invasion and angiogenesis of PDAC cells in 3D-ECM cultures and chorioallantois tumor models by stimulating expression and secretion of matrix-metalloproteinase 7 and 9 (MMP7/9). MMP9 also enhances PKD2-mediated tumor angiogenesis releasing extracellular matrix-bound VEGF-A. We thus suggest high PKD2 expression and loss of PKD1 may be beneficial for tumor cells to enhance their matrix-invading abilities. In our recent study we demonstrate for the first time PKD1 and 2 isoform-selective effects on pancreatic cancer cell invasion, in-vitro and in-vivo, defining isoform-specific regulation of PKDs as a major future issue.
    05/2014; 4(3). DOI:10.4161/bioa.29273
  • T Seufferlein, A Kleger, S Nitschmann
    Der Internist 03/2014; · 0.27 Impact Factor
  • A Kleger, L Perkhofer, T Seufferlein
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death in the Western world. Owing to a lack of specific symptoms and no accessible precursor lesions, primary diagnosis is commonly delayed, resulting in only 15%-20% of patients with potentially curable disease. The standard of care in advanced pancreatic cancer has improved. Apart from gemcitabine (plus erlotinib), FOLFIRINOX and the combination of gemcitabine plus nab-paclitaxel are novel and promising therapeutic options for patients with metastatic PDAC. A better molecular understanding of pancreatic cancer has led to the identification of a variety of potential molecular therapeutic targets. Many targeted therapies are currently under clinical evaluation in combination with standard therapies for PDAC. This review highlights the current status of targeted therapies and their potential benefit for the treatment of advanced PDAC.
    Annals of Oncology 03/2014; 25(7). DOI:10.1093/annonc/mdu013 · 6.58 Impact Factor
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    ABSTRACT: In order to improve the quality of treatment for cancer patients the German Cancer Society (Deutsche Krebsgesellschaft) implemented a certification system for oncological care institutions. The certified colorectal cancer centers present the structures, processes and results of their network in the framework of an auditing procedure. The current benchmarking report by the certified centers reflects the centers' reference results over a period of 3 years. The figures included in the benchmarking report reflect the areas of interdisciplinary collaboration, guideline-compliant treatment, and expertise of the main treatment partners. High percentages were shown for indicators reflecting pretreatment and postoperative case presentations in multidisciplinary team meetings (91.8 % or 98.1 %), psycho-oncologic care (54.8 %) as well as social service counseling (77.1 %). Good quality of the TME rectal specimen and adequate lymph-node retrieval (12 lymph nodes at least) was achieved by 93 % or 96.6 % of the centers. Adjuvant chemotherapy (colon, Union for International Cancer Control [UICC] stage III) or neoadjuvant radiotherapy or chemoradiotherapy (rectum, UICC stages II and III) received 73.7 % or 80 % of relevant patients. Quotas of anastomotic leakage in the colon or rectum were 4.4 % or 7.6 %, whereas postoperative mortality amounted to 2.6 %. The present analysis of the results, together with the centers' statements and the auditors' reports, shows that most of the targets for indicator figures are being better met over the course of time. In addition, however, there is a clear potential for improvement and the centers are verifiably addressing this. A transparent presentation of the quality of care and reflection on and discussion of the results among the treatment partners in the certified network and with the auditors during the certification process may contribute to constant quality improvement in oncological care.
    International Journal of Colorectal Disease 03/2014; 29(4). DOI:10.1007/s00384-014-1842-x · 2.24 Impact Factor
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    ABSTRACT: Pluripotent stem cells possess a remarkable unlimited self-renewal capacity and offer unparalleled in vitro differentiation potential. This provides a unique model system not only to study early human development but also gives renewed hope in terms of developing cell therapies and regenerative medicine. S. Yamanaka, a medical doctor and researcher, reported the possibility of reprogramming somatic cells to so-called induced pluripotent stem cells via the ectopic expression of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc. This Nobel Prize winning work has since revolutionized stem cell research and paved the way for countless new avenues within regenerative medicine. This includes disease modeling in a patient-specific context with the ultimate aim of individually tailored pharmaceutical therapy. Additionally, genetic correction studies have rapidly increased in basic science and thus there is hope that these can be effectively and efficiently translated into clinical applications. Addressing the medical community this review gives a broad general overview about the state of the research field and possible clinical applications of pluripotent stem cells.
    Der Internist 02/2014; 55(4). DOI:10.1007/s00108-013-3397-2 · 0.27 Impact Factor

Publication Stats

4k Citations
992.53 Total Impact Points

Institutions

  • 2015
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2002–2015
    • Universität Ulm
      • • Institute of Orthopaedic Research and Biomechanics
      • • Clinic of Internal Medicine I
      • • Department of Internal Medicine
      Ulm, Baden-Württemberg, Germany
    • KU Leuven
      • Faculty of Medicine
      Leuven, VLG, Belgium
  • 2006–2014
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
    • Catholic University of Louvain
      Walloon Region, Belgium
  • 2013
    • Deutsche Krebsgesellschaft e.V.
      Berlín, Berlin, Germany
  • 2008–2013
    • Martin Luther University of Halle-Wittenberg
      • Clinic for Internal Medicine I
      Halle-on-the-Saale, Saxony-Anhalt, Germany
    • Universitäts- und Rehabilitationskliniken Ulm
      Ulm, Baden-Württemberg, Germany
  • 2009–2012
    • Universitätsklinikum Halle (Saale)
      Halle-on-the-Saale, Saxony-Anhalt, Germany
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2011
    • Azienda Ospedaliero-Universitaria Pisana
      Pisa, Tuscany, Italy
  • 2007
    • Otto-von-Guericke-Universität Magdeburg
      • Clinic for Gastroenterology, Hepatology and Infectiology
      Magdeburg, Saxony-Anhalt, Germany
  • 2005
    • Prosper-Hospital Recklinghausen
      Recklinghausen, North Rhine-Westphalia, Germany
  • 2003
    • Klinikum Augsburg
      • II. Department of Internal Medicine
      Augsberg, Bavaria, Germany