Research Group Experimental Neurooncology

Research Group Experimental Neurooncology

Prof. Dr. med. Frank Winkler

Tumor microtubes and brain tumor progression

 

Our group is interested in clinically relevant, but also basic questions in brain tumor research. The focus lies on malignant glioma and brain metastasis. To optimally study brain tumor initiation and progression, we have refined animal models using in vivo two-photon microscopy in our DKFZ lab. This methodology allows to study brain cancer cell populations and their dynamic behavior over many months, including their cellular components, gene expression, blood vessels, glia cells, neurons, intercellular communications, and important physiological and therapeutical parameters like hypoxia, blood flow velocity, and vascular permeability. This unique approach makes it possible to investigate dynamic interactions of cells, and the key mechanisms in a live organism over long periods of time in high resolution.

We currently pursue the following main research projects:

  • The role of tumor microtubes in brain tumor progression: We discovered that ultra-long and ultra-thin membrane extensions of astrocytoma (including glioblastoma) cells are highly relevant for tumor progression and resistance to therapies (Osswald et al., Nature 2015). The resulting multicellular tumor network allows intensive intercellular communication, and better cellular homeostasis, which results in resistance to radiotherapy. In ongoing projects, we aim to better understand 1) whether tumor microtubes are also relevant for resistance to other treatment modalities; 2) whether and how the astrocytoma network communicates with nonmalignant cells; 3) how tumor microtubes, and the functional network they form, can be optimally targeted by therapies – to reduce the notorious treatment resistance of many brain tumors (http://www.cell.com/trends/cancer/abstract/S2405-8033%2815%2900084-9).
  • The role of cancer stem cells for the brain metastatic cascade: This DFG supported project uses reporter systems for cancer cell stemness and investigates whether breast cancer stem cells are mandatory for the single steps of brain metastasis formation, and whether their inhibition is of therapeutic benefit for the disease.
  • Angiogenesis and invasion of gliomas: primary cell culturs of glioblastoma patients are investigated with respect to their invasion into normal brain, and its interdependence with tumor angiogenesis. In cooperation projects with industry, we investigate how modern antiangiogenic therapies modulate growth and invasion of gliomas, and their response to chemo- and radiotherapy.
  • Brain metastases prevention by anti-angiogenic therapy
  • The role of the blood-brain barrier in brain tumor therapy

Selected Publications

  • Matthias Osswald, Erik Jung, Felix Sahm, Gergely Solecki, Varun Venkataramani, Jonas Blaes, Sophie Weil, Heinz Horstmann, Benedikt Wiestler, Mustafa Syed, Lulu Huang, Miriam Ratliff, Kianush Karimian Jazi, Felix T. Kurz, Torsten Schmenger, Dieter Lemke, Miriam Gömmel, Martin Pauli, Yunxiang Liao, Peter Häring, Stefan Pusch, Verena Herl, Christian Steinhäuser, Damir Krunic, Mostafa Jarahian, Hrvoje Miletic, Anna S. Berghoff, Oliver Griesbeck, Georgios Kalamakis, Olga Garaschuk, Matthias Preusser, Samuel Weiss, Haikun Liu, Sabine Heiland, Michael Platten, Peter E. Huber, Thomas Kuner, Andreas von Deimling, Wolfgang Wick und Frank Winkler (2015): Brain tumour cells interconnect to a functional and resistant network. Nature DOI: 10.1038/nature16071
  • von Baumgarten L, Brucker D, Tirniceru A, Kienast Y, Grau S, Burgold S, Herms J, Winkler F (2011). Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells. Clin Cancer Res 17:6192-205.
  • Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert W, Goldbrunner R, Herms J, Winkler F (2010). Real-time imaging reveals the single steps of brain metastasis formation. Nature Medicine 16: 116-22.
  • Winkler F, Kienast Y, Fuhrmann M, von Baumgarten L, Burgold S, Mitteregger G, Herms J (2009). Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis. Glia 57:1306-15.
  • Winkler F, Kozin SV, Tong RT, Chae S, Booth MF, Garkavtsev I, Xu L, Hicklin DK, Fukumura D, di Tomaso E, Munn LL, Jain RK (2004). Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, Angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6: 553-563.

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