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Research Group Experimental Neurooncology

Prof. Dr. med. Frank Winkler

Brain metastasis/Brain tumor cell networks

Cancer Neuroscience of brain tumors and beyond

Our group is interested in clinically relevant, but also basic questions in cancer research, focussing on mechanisms of tumor growth in the brain, and how the nervous system stimulates it in the brain and beyond. An overarching topic of our research is "Cancer Neuroscience", a rapidly evolving field of research. Our traditional focus lies on incurable gliomas, including glioblastoma, and brain metastasis, but extends to other cancer entities now. 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.

Twitter: @Winkler_Lab 

Deutsche Version:

Our research interests are currently focused on four main topics:

  • The role of tumor microtubes (TMs) in brain tumor progression and the neurobiology of malignant glioma (Subgroup leader: Dr. Sophie Heuer (née Weil), Scientists: Dr. Salma Baig, Dr. Miriam Ratliff): We discovered that ultra-long and thin membrane extensions of tumor cells from incurable gliomas (including glioblastomas) which resemble neurites during neurodevelopment 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 (Weil, Neuro Oncol 2017). So far, two neurodevelopmental molecular drivers of TM- and network formation have been identified. In ongoing projects, we aim to understand 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.  In another, increasingly important line of research we aim to "crack the code" of the complex communication patterns in tumor networks. In a first publication we identified pacemaker-like tumor cells that rhythmically generate calcium oscillations, stimulating other network-connected tumor cells via their strategic position in network hubs. This activates specific downstream pathways in the entire tumor network, making brain tumors more aggressive and resilient (Hausmann et al., Nature 2023). This is another recapitulation of a neurodevelopmental mechanism, and potentially a new research field in oncology: "Cancer Rhythmology". Last but not least, the responsible ion channel (KCa3.1) is an interesting therapeutic target. 
  • The role of neuron-glioma synapses for glioma progression and therapy resistance: 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. Further joint work demonstrated the role of network-unconnected glioblastoma cells: they are colonizing the normal brain, hijacking distinct neuronal mechanisms on 3 layers (molecular, cellular invasion, neuron-glioma synapses). Those cells extend 1 or 2 TMs that dynamically scan the brain, and allow fast invasion, later leading to establishment of more stable tumor cell networks (Venkataramani et al., Cell 2022). This work also increases our understanding of the functional relevance of tumor cell heterogeneity in glioblastoma. 
  • Prevention of brain metastasis (Subgroup leader: Dr. Matthia Karreman): We were able to follow brain colonisation by single cancer cells over weeks to months, from vascular arrest to macrometastases formation - in real time and sub-cellular resolution (Kienast et al., Nat Med 2010; Karreman et al., J Cell Sci 2016). Taking advantage of this unique model, we were able to clarify important biological factors of the brain metastatic cascade. We combine expertise in intravital microscopy and correlative light and electron microscopy (Karreman et al, Trends Cell Biol 2016) to unravel the mechanisms of early brain seeding (Karreman et al, Cancer Res 2023) and interactions of brain metastases with their unique microenvironment. Importantly, this research also lead to novel concepts how to target them, preventing brain metastases formation (Feinauer et al, Blood 2020; Tehranian et al, Neuro Oncol 2021). 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. In 2020 the e:Med Juniorverbund Project MelBrainSys has started, which is funded for five years by the German 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.  
  • Interactions between extracranial tumors and the nervous system (Scientists: Dr. Christina Nürnberg, Dr. Chenchen Pan): Based on our findings in the context of cerebral tumor manifestations, we hypothesize that also outside the brain our nervous system has significant impact on the tumor biology of different entities. The overall aim of our novel research focus thus is to shine a light on these interactions e.g. through whole body imaging and thereby identify potentially interesting new therapeutical targets.

Funding: SFB 1389, Unite_Glioblastoma (DFG, German Research Foundation); RTG2099, Hallmarks of Skin Cancer (DFG, DKFZ und UMM); German Cancer Aid (Deutsche Krebshilfe), e:Med Systems Medicine, MelBrainSys (BMBF, Federal Ministry for Education and Research); Hertie Network of Excellence in Clinical Neuroscience (Hertie Foundation).

Selected Publications

  • Venkataramani V*, Karreman MA*, Nguyen LC, Tehranian C, Hebach N, Mayer CD, Meyer L, Mughal SS, Reifenberger R, Felsberg J, Köhrer K, Schubert MC, Westphal D, Breckwoldt MO, Brors B, Wick W, Kuner T#, Winkler F#. Direct excitatory synapses between neurons and tumor cells drive brain metastatic seeding of breast cancer and melanoma. bioRxiv 2024, 2024.01.08.574608; doi: *These authors contributed equally. #These authors contributed equally. *#: Corresponding authors.
  • Heuer SE and Winkler F. Glioblastoma revisited: from neuronal-like invasion to pacemaking. Trends in Cancer 2023 Available via:
  • Winkler F, Venkatesh H S, Amit M, Batchelor T, Demir I E, Deneen B, Gutmann D H, Hervey-Jumper S, Kuner T, Mabbott D, Platten M, Rolls A, Sloan E K, Wang T C, Wick W, Venkataramani V and Monje M. Cancer neuroscience: State of the field, emerging directions. Cell 2023 186 1689–707. Available (open access) via:
  • Karreman MA, Bauer AT, Solecki G, Berghoff AS, Mayer CD, Frey K, Hebach N, Feinauer MJ, Schieber NL, Tehranian C, Mercier L, Singhal M, Venkataramani V, Schubert MC, Hinze D, Hölzel M, Helfrich I, Schadendorf D, Schneider SW, Westphal D, Augustin HG, Goetz JG, Schwab Y, Wick W, Winkler F. Active remodeling of capillary endothelium via cancer cell-derived MMP9 promotes metastatic brain colonization. Cancer Res 2023 doi: 10.1158/0008-5472.CAN-22-3964. Epub ahead of print.
  • Hausmann D, Hoffmann D C, Venkataramani V, Jung E, Horschitz S, Tetzlaff S K, Jabali A, Hai L, Kessler T, Azorín D D, Weil S, Kourtesakis A, Sievers P, Habel A, Breckwoldt M O, Karreman M A, Ratliff M, Messmer J M, Yang Y, Reyhan E, Wendler S, Löb C, Mayer C, Figarella K, Osswald M, Solecki G, Sahm F, Garaschuk O, Kuner T, Koch P, Schlesner M, Wick W and Winkler F. Autonomous rhythmic activity in glioma networks drives brain tumour growth Nature 2023 613(7942):179-186 DOI: 10.1038/s41586-022-05520-4 Available via:
  • Venkataramani V, Yang Y, Schubert MC, Reyhan E, Tetzlaff SK, Wißmann N, Botz M, Soyka SJ, Beretta CA, Pramatarov RL, Fankhauser L, Garofano L, Freudenberg A, Wagner J, Tanev DI, Ratliff M, Xie R, Kessler T, Hoffmann DC, Hai L, Dörflinger Y, Hoppe S, Yabo YA, Golebiewska A, Niclou SP, Sahm F, Lasorella A, Slowik M, Döring L, Iavarone A, Wick W, Kuner T*, Winkler F*. Glioblastoma hijacks neuronal mechanisms for brain invasion. Cell 2022 185(16):2899-2917 DOI: 10.1016/j.cell.2022.06.054  
  • Venkataramani V*, Schneider M*, Giordano FA, Kuner T, Wick W, Herrlinger U*, Winkler F*.
    Disconnecting multicellular networks in brain tumours. Nature Reviews Cancer 2022 22(8):481-491
    DOI: 10.1038/s41568-022-00475-0
  • Tehranian C, Fankhauser L, Harter PN, Ratcliffe CDH, Zeiner PS, Messmer JM, Hoffmann DC, Frey K, Westphal D, Ronellenfitsch MW, Sahai E, Wick W, Karreman MA*, Winkler F*. The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis. Neuro Oncol 2021 24(2):213-225 DOI: 10.1093/neuonc/noab159
  • Jung E, Osswald M, Ratliff M, Dogan H, Xie R, Weil S, Hoffmann DC, Kurz FT, Kessler T, Heiland S, von Deimling A, Sahm F, Wick W, Winkler F. Tumor cell plasticity, heterogeneity, and resistance in crucial microenvironmental niches in glioma. Nat Commun 2021 12(1):1014. doi: 10.1038/s41593-019-0540-y.
  • Berghoff AS, Liao Y, Karreman MA, Ilhan-Mutlu A, Gunkel K, Sprick MR, Eisen C, Kessler T, Osswald M, Wünsche S, Feinauer M, Gril B, Marmé F, Michel LL, Bago-Horvath Z, Sahm F, Becker N, Breckwoldt MO, Solecki G, Gömmel M, Huang L, Rübmann P, Thome CM, Ratliff M, Trumpp A, Steeg PS, Preusser M, Wick W, Winkler F. Identification and Characterization of Cancer Cells That Initiate Metastases to the Brain and Other Organs. Mol Cancer Res. 2021 19(4):688-701. doi: 10.1158/1541-7786.MCR-20-0863.
  • Feinauer MJ*, Schneider SW*, Berghoff AS, Robador JR, Tehranian C, Karreman MA, Venkataramani V, Solecki G, Grosch JK, Gunkel K, Kovalchuk B, Mayer FT, Fischer M, Breckwoldt MO, Brune M, Schwab Y, Wick W, Bauer AT*, Winkler F* (2020). Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model. Blood 2020; doi 10.1182/blood.2020005710
  • Monje M, Borniger JC, D'Silva NJ, Deneen B, Dirks PB, Fattahi F, Frenette PS, Garzia L, Gutmann DH, Hanahan D, Hervey-Jumper SL, Hondermarck H, Hurov JB, Kepecs A, Knox SM, Lloyd AC, Magnon C, Saloman JL, Segal RA, Sloan EK, Sun X, Taylor MD, Tracey KJ, Trotman LC, Tuveson DA, Wang TC, White RA & Winkler F. Roadmap for the Emerging Field of Cancer Neuroscience. Cell 2020; 181, 219-222
  • Jung E, Alfonso J, Osswald M, Monyer H, Wick W, Winkler F. Emerging intersections between neuroscience and glioma biology. Nat Neurosci 2019 22(12):1951-1960.
  • Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, Körber C, Kardorff M, Ratliff M, Xie R, Horstmann H, Messer M, Paik SP, Knabbe J, Sahm F, Kurz FT, Acikgöz AA, Herrmannsdörfer F, Agarwal A, Bergles DE, Chalmers A, Miletic H, Turcan S, Mawrin C, Hänggi D, Liu HK, Wick W, Winkler F*, Kuner T*. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 2019 573(7775):532-538.
  • 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. 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 2016; 129 444–56.
  • Karreman MA, Hyenne V, Schwab Y, Goetz JG. Intravital Correlative Microscopy: Imaging Life at the Nanoscale. Trends Cell Biol. 2016 26(11):848-863. doi: 10.1016/j.tcb.2016.07.003.
  • 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
  • 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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