Cancer Neuroscience
Overview
The central interest of our group is to understand how cancers integrate into the nervous system, electrically, structurally and molecularly, and how this integration can be turned against the tumor.
Incurable brain cancers are connected systems. Tumor cells organize into functional multicellular networks, and these networks are themselves embedded in the neural connectome of the patient. We discovered that neurons form direct glutamatergic synapses onto glioma cells (Venkataramani et al., Nature 2019; Venkataramani et al., Cell 2022). These malignant synapses are fully functional: they depolarize tumor cells, drive calcium signaling through the network, and act as the pacemaker of invasion and proliferation in every model system and every piece of patient-derived human tissue we have examined so far. Cancer, in other words, does not only colonize the brain; it learns to speak its language.
This reframes the disease and, more importantly, the therapeutic problem. If tumor progression depends on electrical and synaptic integration into a neural circuit, then that circuit becomes a target. It is a target accessible with drug classes that neurology and psychiatry have used safely for decades, and one that is fundamentally different from every mechanism oncology has attacked so far.
To pursue this, we develop and combine methods across scales and deliberately apply them on both sides of the translational gap, in refined animal models and directly in living and preserved human brain tumor tissue: long-term intravital two-photon and multiphoton imaging, electrophysiology and calcium imaging, super-resolution and expansion microscopy, correlative volume electron microscopy, and single-cell and spatial multi-omics, increasingly integrated on one and the same sample.
We currently pursue the following main research projects:
Decoding the cancer connectome
Which neurons connect to which tumor cells, and what determines that choice? We map the wiring diagram of brain tumors at the level of circuits, cells and individual synapses, combining functional imaging and electrophysiology with ultrastructural and molecular analysis of the neuron-glioma synapse. To move from correlation to identity, we are building genetically encoded connectivity-labeling systems that mark every cell in physical contact with a tumor cell, so that the tumor's cellular partners can be read out directly rather than inferred. The goal is a molecular and physiological map of how a cancer plugs itself into a brain.
How cancer cells remodel the brain
Tumor cells are not passive listeners on the network. They actively sculpt the neural tissue around them, remodeling axons and synapses, shifting the balance of excitation and inhibition, and rewiring circuits in their favor. We study the subcellular machinery that makes this possible, including the local, compartmentalized protein synthesis that runs inside tumor microtubes at the invasive front and generates functional heterogeneity within a single tumor. This work connects directly to the clinical realities of our patients: tumor-associated epilepsy, network dysfunction, and cognitive decline are not side effects of the disease but readouts of the same mechanism that drives it.
Human Cancer Neuroscience
A mechanism only matters if it holds in patients. We therefore bring the full methodological arsenal of neuroscience to human brain tumor tissue: multi-region, MRI-registered sampling across tumor core, infiltration zone and access cortex; functional recordings from resected living tissue; patient-derived cell lines and organoids; and integrated ultrastructural and spatial-omics analysis of the same specimen. Together with neurosurgical partners in Germany, Europe and beyond, we are establishing standardized protocols and a shared tissue resource for this young field, and from it an atlas of the human cancer connectome.
Neuroscience-instructed cancer therapies
Every layer of this work is aimed at one endpoint: disconnecting the tumor. We test whether interrupting synaptic input, network connectivity and activity-dependent signaling slows tumor growth and restores sensitivity to radiotherapy and chemotherapy, including with compounds that are already clinically approved for neurological indications and can therefore reach patients quickly. In parallel, we develop the imaging and molecular biomarkers needed to identify the patients in whom the tumor's neural dependence is strongest, and to prove target engagement in early clinical trials.
Our group is interdisciplinary by necessity: physicians, neuroscientists, oncologists, molecular biologists, physicists and computational scientists work side by side, with the operating room, the microscope and all molecular tools within walking distance of each other. If you are interested in joining us, collaborating, or supporting this work, we would be glad to hear from you.
Members
Lab Manager
Verena Buchert
Postdocs/Physician-Scientists
Dr. med. Obada Alhalabi
Dr. rer. nat. Nikolas Layer
Dr. med. Benedikt Plaack
Dr. med. Marian Touet
Dr. med. Yvonne Yang
PhD Students
Marvin Porsiel
Atefeh Pourkhalili
Medical Students
Mahammad Bashirov
Marc Dehler
Robert Denninger
Robin Dietl
Nina Drewa
Felix Kaiser
Elijah Keifert
Maximilian Lasotta
Ben-Ole Levermann
Hazel Liu
Madlena Ly
Henri Olldashi
Rangel Pramatarov
Ekin Reyhan
Vivek Sahu
Julian Schroers
Nirosa Sivapalan
Niklas Wißmann
Research Technician
Daniela Pimonov
Selected Publications
1) Tetzlaff, S. K., Reyhan, E., Layer, N., Bengtson, C. P., Heuer, A., Schroers, J., Faymonville, A. J., Langeroudi, A. P., Drewa, N., Keifert, E., Wagner, J., Soyka, S. J., Schubert, M. C., Sivapalan, N., Pramatarov, R. L., Buchert, V., Wageringel, T., Grabis, E., Wißmann, N., Alhalabi, O. T., Botz, M., Bojcevski, J., Campos, J., Boztepe, B., Scheck, J. G., Conic, S. H., Puschhof, M. C., Villa, G., Drexler, R., Zghaibeh, Y., Hausmann, F., Hänzelmann, S., Karreman, M. A., Kurz, F. T., Schröter, M., Thier, M., Suwala, A. K., Forsberg-Nilsson, K., Acuna, C., Saez-Rodriguez, J., Abdollahi, A., Sahm, F., Breckwoldt, M. O., Suchorska, B., Ricklefs, F. L., Heiland, D. H. & Venkataramani, V. $ Cell, 188, 390-411.e36. (2025)
2) Venkataramani, V.*, Tanev, D.I., Strahle, C., Studier-Fischer, A., Fankhauser, L., Kessler, T., Korber, C., Kardorff, M., Ratliff, M., Xie, R., et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532-538. (2019)
3) Venkataramani, V.*, Yang, Y., Schubert, M.C., Reyhan, E., Tetzlaff, S.K., Wissmann, N., Botz, M., Soyka, S.J., Beretta, C.A., Pramatarov, R.L., et al.. Glioblastoma hijacks neuronal mechanisms for brain invasion. Cell 185, 2899-2917 e2831. (2022)
4) Schubert, M. C. … Prevedel, R.*, Venkataramani, V.* Deep intravital brain tumor imaging enabled by tailored three-photon microscopy and analysis. Nature Communications, 15, 7383. (2024)
5) Venkataramani, V. *,# et al. Direct excitatory synapses between neurons and tumor cells drive brain metastatic seeding of breast cancer and melanoma. bioRxiv, 2024.2001.2008.574608, doi:10.1101/2024.01.08.574608 (2024).
6) Venkataramani, V.#, Herrmannsdorfer, F.#, Heilemann, M., and Kuner, T. (2016). SuReSim: simulating localization microscopy experiments from ground truth models. Nat Methods 13, 319-321.
7) Venkataramani, V.#, Kardorff, M.#, Herrmannsdorfer, F., Wieneke, R., Klein, A., Tampe, R., Heilemann, M., and Kuner, T. (2018). Enhanced labeling density and whole-cell 3D dSTORM imaging by repetitive labeling of target proteins. Sci Rep 8, 5507.
8) Schubert, M. C., Wick, W. & Venkataramani, V. $ Performance of Large Language Models on a Neurology Board–Style Examination. JAMA Network Open6, e2346721-e2346721, doi:10.1001/jamanetworkopen.2023.46721 (2023).
9) Schroers, J#, Yang, Y#….Venkataramani,V.$ Voxel-accurate MRI-microscopy correlation enables AI-powered prediction of brain disease states. Theranostics, accepted
10) Jeong, D., Danielli, S. G., Maaß, K. K., Ghasemi, D. R., Tetzlaff, S. K., Reyhan, E., Oliveira de Biagi-Junior, C. A., Neyazi, S., Nascimento, A., Haase, R., Lo Cascio, C., Englinger, B., Jiang, L. Nguyen, C. M., Baumgartner, A.-C., Castellani, S., Rozowsky, J. S., Hack, O. A., Shaw, M. L., Lotsch-Gojo, D., Bruckner, K., Pfister, S. M., Kool, M., Nowakowski, T. J., Gojo, J, Baird, L., Alexandrescu, S., Pajtler, K. W.*, Venkataramani, V.*, Filbin, M. G.* (2024). Single-cell multidimensional profiling of tumor cell heterogeneity in supratentorial ependymomas. Nature, in principle accepted.
$ Corresponding Author, * Co-corresponding/co-senior author, # Equal contribution