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PD Dr. Dirk Schmidt-Arras

Dirk Schmidt-Arras
Dirk Schmidt-Arras
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Inflammation and Cancer
Research
Overview

Cancer is one of the leading causes of death worldwide. Very often patients present at advanced stages of disease with tumor cell dissemination at distant organ sites, a process called metastasis. For many tumor entities an efficient curative therapy is still lacking.
Figur 1 Growth of normal tissue cells is regulated by intercellular and intracellular communication. Malignant tumor cells have developed stra­te­gies to escape these re­gu­la­to­ry mechanisms.
In close collaboration with clinicians we're in­ves­ti­ga­ting aberrantly activated signaling cues in cancer with the final goal to find new con­cepts for therapeutic intervention in malignant diseases.
To this aim we're applying state-of-the-art cell bi­o­log­i­cal and biochemical methods and an­a­lyse potential drug targets in murine tumor models.

 
Spatial intracellular signalling of oncogenic cytokine receptors
Figur 2The cytokine interleukin-6 (IL-6) plays important roles in inflammation and re­gen­er­at­ion. In complex with the IL-6 receptor it binds to the signalling subunit gp130 which is expressed in all cell types. Recently, deletion mutants of gp130 have been identified in inflammatory hepatocellular adenomas. The deletions oc­cur­red predominantly within the IL-6 binding loop in the D2 domain of the gp130 ex­tracellular domain. These mutations rendered gp130 constitutively active in a li­gand-independent manner.

Figure 3 Using bioinformatics and biochemical approaches we identified amino acid re­si­dues that are critical to keep gp130 wild­type in an inactive state and pro­posed a model in which displacement of the D2 EF loop is a pre­requisite for gp130 activation [1]. We furthermore no­ted that gp130 ΔYY is predominantly lo­ca­lised in the en­do­plas­mic re­ti­cu­lum and early endosomes (Fig., lower panel). Maturation kinetics of gp130 ΔYY are dra­matically slowed down due to folding de­fects (Fig., upper panel) and therefore gp130 ΔYY is entrapped in the ER quality con­trol system. We could fur­ther­more show that gp130 ΔYY signals from in­tra­cel­lu­lar compartments [2].

We currently analyse if aberrant localisation of active cytokine receptors is responsible for downstream signal quality und subsequent oncogenic processes.

Cooperations:
  • Frank-D. Böhmer, Institute for Molecular Cell Biology, University Jena
  • Martin Zacharias, Physical Department, TU München
  • Joachim Grötzinger, Institute of Biochemistry, CAU Kiel
Literature:
  1. Schütt, A. et al., Biochem. J. (2013) 450(3):487-96.
  2. Schmidt-Arras, D. et al., J. Cell Sci. (2014) 127 (Pt 2):341-53.
  3. Schmidt-Arras, D. et al., Blood (2009) 113(15):3568-76.
  4. Choudhary, C. et al., Mol Cell (2009) 36(2):326-39.
  5. Schmidt-Arras, D. et al., Mol. Cell Biol. (2005) 25(9):3690-703.
The role of ADAM-proteases in liver pathologies

The family of ADAM (A disintegrin and metalloprotease) proteases has been implicated in a variety of signalling processes. Ectodomain shedding of cytokines like e.g. TNFα, growth-factors like e.g. TGFα and receptors like e.g. Notch have been shown to be mediated by ADAM10 and ADAM17. Our general aim is to identify signaling pathways that can be exploited for the treatment of liver pathologies.

Figure 4 We generated mice deficient for ADAM10 in the liver pa­ren­chy­ma. Interestingly, these mice spontaneously develop liver fibrosis with increased collagen de­po­si­tion during ageing (see Figure). In close collaboration with groups from Prague and Jerusalem, we are cur­rent­ly investigating the underlying signaling cues and potential substrate molecules of ADAM10. We fur­ther­more analyse if these mice are more prone to liver tu­mor formation and if impaired ADAM10 sig­na­ling can be detected in human liver tumors.

Figure 5 Using a common chemical-induced murine liver carcinogenesis model we are investigating the role of ADAM17 and downstream signaling pathways during the formation of hepatocellular carcinoma (liver can­cer) and other liver malignancies. Thereby, in co­op­er­at­ion with the MOIN CC facility and the department of radiology we are applying state-of-the-art imaging technologies (see Figure).

Cooperations:

  • Karel Chalupský, Radislav Sedlácek, Laboratory of Transgenic Models of Diseases, Institute of Mo­le­cu­lar Genetics of the ASCR, Prague, Czech Republic
  • Daniel Goldenberg, Eithan Galun, Goldyne Savad Institute of Gene Therapy, Hadassah Medical Centre, Jerusalem, Israel
  • Roja Barikbin, Gabi Sass, Institute of Experimental Immunology and Hepatology, UKE Hamburg
  • Erçan Akgün, Boris Fehse, Bone Marrow Transplantation Unit, UKE Hamburg
  • Rabea Wagener, Anke Bergmann, Reiner Siebert, Institute of Human Genetics, UKSH Kiel
  • Carola Heneweer, Department of Radiology and Neuroradiology, UKSH Kiel
  • Kristin Koetz, Susann Boretius, Department of Biomedical Imaging, UKSH Kiel
  • Holger Kalthoff, Institute of Experimental Oncology, UKSH Kiel
  • Thomas Becker, Department of Surgery, UKSH Kiel

The impact of ADAM-proteases and its regulators on the metastatic process

Figure 6 ADAM proteases have been implicated in a number of tumors. However, little is known about the role of ADAM proteases in the tu­mor stroma and cells of the metastatic niche. We found that loss of particular ADAM pro­teases in cells of the metastatic niche pro­tects mice from experimental tumor metastasis. We are currently analysing the un­der­ly­ing mechanisms and potential sub­strates of ADAMs responsible for the ob­served effects. We are furthermore trying to identify ADAM proteases can be used po­ten­tial drug targets for inflammation-as­so­ci­ated cancers and tumor metastasis. Tetraspanins are proteins that span the plasmamembrane four times. Some of them have been shown to interact with the protease ADAM10 [6,7]. Several members of the tetraspanin family have been as­so­ci­ated with malignant pathologies. We're currently in­ves­ti­ga­ting the implication of selected tetraspanins in the regulation of ADAM proteases and its role in malignant liver pa­tho­lo­gies.

Cooperations:
  • Ralf Schwanbeck, Johannes Prox, Christoph Becker-Pauly, Institute of Biochemistry, CAU Kiel
  • Kristoffer Riecken, Boris Fehse, Bone Marrow Transplantation Unit, UKE Hamburg
  • Daniela Dreymüller, Andreas Ludwig, Institute of Pharmacology and Toxicology, RWTH Aachen
  • Haissi Cui, Achim Krüger, Institute of Experimental Oncology and Therapy Research, University Hospital, TU München
Literature:
  1. Prox J. et al., Cell Mol Life Sci. (2012) 69(17):2919-32.
  2. Dornier, E. et al., J Cell Biol. (2012) 199(3):481-96.