Experimental Neurooncology

Tumor networks in brain metastasis (Teamleader: 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. 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 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. https://www.dkfz.de/de/presse/pressemitteilungen/2020/dkfz-pm-20-21c-Hirnmetastasen-bei-schwarzem-Hautkrebs-BMBF-foerdert-Forschung-zu-neuen-Behandlungsstrategien.php  

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).

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. https://www.dkfz.de/en/presse/pressemitteilungen/2019/dkfz-pm-19-41c-Neurons-promote-growth-of-brain-tumor-cells.php 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. https://www.klinikum.uni-heidelberg.de/newsroom/brain-tumor-cells-invade-the-brain-as-neuronal-free-riders/ 

Interactions between extracranial tumors and the nervous system (Scientist: Dr. Christina Nürnberg): 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.