Research Group Experimental Neurooncology

Prof. Dr. med. Frank Winkler

Brain tumor cell networks

Deutsche Version:

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.


Our research interests are currently focused on two main topics:

  • The role of tumor microtubes (TMs) in brain tumor progression and the neurobiology of malignant glioma (responsible scientist: Dr. Erik Jung): We discovered that ultra-long and ultra-thin neurite-like 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 and chemotherapy. The communicating tumor cell network is even able to repair itself, which is one mechanism of regrowth after surgical resection. So far, two neurodevelopmental molecular drivers of TM- and network formation have been identified. In ongoing projects, we aim to better 1) whether and how the astrocytoma network communicates with nonmalignant cells, 2) how neurodevelopmental processes are recapitulated in malignant glioma, and 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.
  • Prevention of brain metastasis (responsible scientist: Dr. Matthia Karreman): We were able to follow brain colonization by single cancer cells over weeks to months, from vascular arrest to macrometastases formation - in real time and sub-cellular resolution (Kienast et al., Nature Medicine 2010). Taking advantage of this unique model, we were able to clarify important biological factors of early brain colonization. Importantly, this research also lead to novel concepts how to target them, preventing brain metastases formation. The prevention of this devastating disease in many cancer patients that are at high risk of brain metastases development in the future bears the promise to make a relevant change in oncology. Therefore, a translational research program funded by the German Cancer Aid was initiated, with the aim to explore specific pathways and targeted therapies to lay the ground for a future brain metastases prevention study: prevent_BM.

Selected Publications

  • Jung, E., Alfonso, J., Osswald, M., Monyer, M., Wick, W., Winkler, F. Emerging intersections between neuroscience and glioma biology. Nat Neurosci (2019).  doi:10.1038/s41593-019-0540-y
  • Venkataramani, V., Tanev, D.I., Strahle, C., [...], Wick, W., Winkler, F.*, Kuner, T.* Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532–538 (2019).
  • Winkler F, Wick W. Harmful networks in the brain and beyond. Science 2018;359:1100-1101 (
  • Osswald M, Jung E, Sahm F, Solecki G, Venkataramani V, Blaes J, Weil S, Horstmann H, Wiestler B, Syed M, Huang L, Ratliff M, Karimian Jazi K, Kurz FT, Schmenger T, Lemke D, Gommel M, Pauli M, Liao Y, Haring P, Pusch S, Herl V, Steinhauser C, Krunic D, Jarahian M, Miletic H, Berghoff AS, Griesbeck O, Kalamakis G, Garaschuk O, Preusser M, Weiss S, Liu H, Heiland S, Platten M, Huber PE, Kuner T, von Deimling A, Wick W, Winkler F.  Brain tumour cells interconnect to a functional and resistant network. Nature 2015;528:93-8
  • Weil S, Osswald M, Solecki G, Grosch J, Jung E, Lemke D, Ratliff M, Hänggi D, Wick W, Winkler F (2017). Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas. Neuro Oncol 2017;19:1316-26
  • Jung E, Osswald M, Blaes J, Wiestler B, Sahm F, Schmenger T, Solecki G, Deumelandt K, Kurz FT, Xie R, Weil S, Heil O, Thomé C, Gömmel M, Syed M, Häring P, Huber PE, Heiland S, Platten M, von Deimling A, Wick W, Winkler F. Tweety-Homolog 1 Drives Brain Colonization of Gliomas. J Neurosci. 2017;37:6837-6850
  • Osswald M, Blaes J, Liao Y, Solecki G, Gömmel M, Berghoff AS, Salphati L, Wallin JJ, Phillips HS, Wick W, Winkler F. Impact of blood-brain barrier integrity on tumor growth and therapy response in brain metastases. Clin Cancer Res  2016;22: 6078-87
  • von Baumgarten L, Brucker D, Tirniceru A, Kienast Y, Grau S, Burgold S, Herms J, Winkler F. Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells. Clin Cancer Res 2011;17:6192-205
  • Ilhan-Mutlu A, Osswald M, Liao Y, Goemmel M, Reck M, Miles D, Mariani P, Gianni L, Lutiger B, Nendel V, Strock S, Perez-Moreno PD, Thorsen F, von Baumgarten LD, Preusser M, Wick W, Winkler F. Bevacizumab prevents brain metastases formation in lung adenocarcinoma. Molecular Cancer Ther  2016;15:702-710
  • Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert W, Goldbrunner R, Herms J, Winkler F. Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 2010;16:116-122
  • Winkler F, Kozin SV, Tong RT, Chae S, Booth MF, Garkavtsev I, Xu L, Hicklin DK, Fukumura D, di Tomaso E, Munn LL, RK Jain RK. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, Angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004;6:553-563

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