Research Group

Experimental Neurooncology

Prof. Dr. Frank Winkler

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 research

Microscopy of brain metastases and gliomablastoma

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.

Social media: winklerlab.bsky.social (BlueSky) and @Winkler_Lab (X)

Projects

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. https://www.dkfz.de/en/presse/pressemitteilungen/2015/dkfz-pm-15-51-Malignant-network-makes-brain-cancer-resistant.php 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. https://www.dkfz.de/en/presse/pressemitteilungen/2022/dkfz-pm-22-72c-How-brain-tumors-keep-the-beat-and-why-that-makes-them-so-dangerous.php

Funding: SFB 1389, Unite_Glioblastoma (DFG, German Research Foundation)

Selected publications

2024 - Immunity

T lymphocyte recruitment to melanoma brain tumors depends on distinct venous vessels.

Messmer JM, Thommek C, Piechutta M, Venkataramani V, Wehner R, Westphal D, Schubert M, Mayer CD, Effern M, Berghoff AS, Hinze D, Helfrich I, Schadendorf D, Wick W, Hölzel M, Karreman MA*, Winkler F*.

2024 - bioRxiv

Direct excitatory synapses between neurons and tumor cells drive brain metastatic seeding of breast cancer and melanoma.

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#.

2023 - Cell

Cancer neuroscience: State of the field, emerging directions.

2022 - Nature

Autonomous rhythmic activity in glioma networks drives brain tumour growth

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.

2023 - Cancer Research

Active remodeling of capillary endothelium via cancer cell-derived MMP9 promotes metastatic brain colonization.

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.

2022 - Cell

Glioblastoma hijacks neuronal mechanisms for brain invasion.

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*

2019 - Nature

Glutamatergic synaptic input to glioma cells drives brain tumour progression.

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*.

All publications