Research Group Experimental Neurooncology

Prof. Dr. med. Frank Winkler

Brain metastasis/Brain tumor cell networks

Deutsche Version:

https://www.dkfz.de/de/neuroonkologie/Mitarbeiter_AG_Winkler.html

Our group is interested in clinically relevant, but also basic questions in brain tumor research. The focus lies on incurable gliomas, including glioblastoma, 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 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. This unique approach makes it possible to investigate dynamic interactions of cells, associated molecular alterations, and the key mechanisms of tumor progression and resistance in a live organism over long periods of time in high resolution. Moreover, with the addition of novel optogenetic tools, we can now study how interactions with the complex multicellular system that makes a tumor influence key factors of brain tumor biology. Most relevant findings include the discovery of communicating tumor cell networks; hijacking of neurodevelopmental pathways for glioma progression; and key steps of brain metastasis formation.  All in all, by combing these unprecedented insights into brain tumor biology and resistance with patient data and state-of-the-art molecular diagnostics, we aim to provide a framework for a better understanding of the central traits of malignancy of these challenging diseases, with the ultimate aim to develop novel therapeutic concepts.

 

 

Our research interests are currently focused on three 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. https://www.dkfz.de/en/presse/pressemitteilungen/2015/dkfz-pm-15-51-Malignant-network-makes-brain-cancer-resistant.php
  • The role of neuron-glioma synapses for glioma progression and therapy resistance (responsible scientist: Dr. Varun Venkataramani): Glioma cells and TM-connected glioma cell networks form bona-fide excitatory synapses with neurons, with the glioma cell as the postsynaptic partner. Those neuron-glioma synapses generate many of the intercellular calcium waves that are typical for TM-connected glioma cell networks, and ultimately stimulate glioma growth and invasion (collaboration with the lab of Th. Kuner, Neuroanatomy Heidelberg: Venkataramani et al., Nature 2019; published back-to-back with Venkatesh et al., Nature 2019). Those neuron-glioma synapses that can be found throughout all animal models of incurable gliomas so far, and also in resected patient tissue, present a novel target for anti-tumor therapies. https://www.dkfz.de/en/presse/pressemitteilungen/2019/dkfz-pm-19-41c-Neurons-promote-growth-of-brain-tumor-cells.php
  • 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; Karreman et al., 2016). 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. https://www.dkfz.de/de/presse/pressemitteilungen/2017/dkfz-pm-17-53c2-Forschungsziel-Gehirnmetastasen-verhindern.php
    • In 2020 the e:Med Juniorverbund Project MelBrainSys has started, which is funded for five years by the Geman Federal Ministry for Education and Research (BMBF). This collaboration with the University Hospital Dresden aims to identify and target driver candidates of melanoma brain metastasis.  

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 (http://science.sciencemag.org/cgi/rapidpdf/359/6380/1100?ijkey=YCLPQTZ3ST8R2&keytype=ref&siteid=sci)
  • 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
  • Karreman M A, Mercier L, Schieber N L, Solecki G, Allio G, Winkler F, Ruthensteiner B, Goetz J G and Schwab Y 2016 Fast and precise targeting of single tumor cells in vivo by multimodal correlative microscopy. Journal of Cell Science 129 444–56 (2016).
  • 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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