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Neurologie und Poliklinik

EXPERIMENTAL NEUROONCOLOGY

 

OVERVIEW

The central interest of the research group is to understand how primary and metastatic tumors progress in the brain, and how this information can be used to improve therapies. The research focus lies on clinically relevant, but also basic questions in brain tumor research; another strong interest lies on dynamic interactions of brain resident and immune cells during neuroinflammation. To study the initiation, progression and therapeutic responses of brain diseases of the central nervous system, we have established refined animal models using in vivo two-photon microscopy in our DKFZ lab. This methodology allows studying 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 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.

The role of cancer stem cells for the brain metastatic cascade: By using reporter systems for cancer cell stemness, we discovered that only a small subpopulation of breast cancer cells is capable of performing the single steps of brain metastasis formation. A novel molecular player for brain colonization of these cells was discovered, providing a new approach for a targeted therapy against brain colonization by circulating tumor cells.

Angiogenesis and invasion of gliomas: 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: This novel approach, supported by results from own previous work (Kienast Nat Med 2010; Ilhan-Mutlu Mol Cancer Ther 2016), appears to be a clinically feasible concept for certain tumor entities, and is consequently being explored at the moment as a translational research concept.

The role of the blood-brain barrier in brain tumor therapy: The impact of calcium homeostasis on neuronal cell damage in the retina during autoimmune disease: As part of the research group FOR 2289, we use a novel methodology to perform intravital imaging of the live retina to understand the cascade of neurodegeneration during optic neuritis.

 

Future work will focus on how to translate these findings into improved therapies for brain tumor patients, with a specific focus on tumor microtube targeting, and brain metastases prevention.

 

 

 

Using in vivo two-photon microscopy, a laser beam was used to kill one glioblastoma cell (dashed circle) that is connected to other tumor cells with fine membrane tubes ("tumor microtubes"). The reaction of the tumor cell network to this loss is remarkable: a new tumor microtube is formed (arrowheads), a distant network cell divides, and the new nucleus (star) travels through the microtube to the very place where the dead network member was located. After 60 hours, the tumor cell network has repaired itself. Inhibition of this process is currently explored to decrease treatment resistance of brain tumors.

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: Brain tumour cells interconnect to a functional and resistant network. Nature 2015;528(7580):93-8

 

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 (2016). Bevacizumab prevents brain metastases formation in lung adenocarcinoma. Molecular Cancer Ther 2016;15(4):702-10

 

Osswald M, Baes J, Liao Y, Solecki G, Gömmel M, Berghoff A-S, Salphati L, Wallin J, Phillips HS, Wick W, Winkler F. Impact of blood-brain barrier integrity on tumor growth and therapy response in brain metastases. Clinical Cancer Research 2016;15(4):702-10 4

 

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. Nature Medicine 2010;16(1):116-22 5

 

Lanz TV, Becker S, Osswald M, Bittner S, Schuhmann MK, Opitz CA, Gaikwad S, Wiestler B, Litzenburger UM, Sahm F, Ott M, Iwantscheff S, Grabitz C, Mittelbronn M, von Deimling A, Winkler F, Meuth SG, Wick W, Platten M. Protein kinase Cbeta as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis. PNAS 2013;110(36):14735-40

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€CONTACT

Frank Winkler

+49 (0) 6221 – 56 7504

Frank.Winkler@med.uni-heidelberg.de

www.dkfz.de/en/neuroonkologie/AG_Winkler.html

 

GROUP MEMBERS

Anna Berghoff

Manuel Feinauer

Julia Grosch

Kianush Jazi

Erik Jung

Matthias Osswald

Miriam Ratliff

Gergely Solecki.

Daniel Weber

Sophie Weil

Frank Winkler

Ruifan Xie