Research
Cellular mechanisms and molecular control of tumor-host tissue interaction and invasion in medulloblastoma
The biological principles of tumor-host tissue interactions in MB and the key molecular regulators of cellular processes and morphological alterations that contribute to tumor growth and tissue invasion are poorly understood. Specifically, how MB tumor cells "communicate" with cells in the cerebellar microenvironment and how the microenvironment responds is poorly understood. In addition to soluble chemical factors, tumor cells release extracellular vesicles (EVs) and extend tunneling nanotubes (TNTs), which may enable the effective transfer of chemical information between different cellular entities.
Therefore, the primary objective of this study is to characterize the molecular control of EV biogenesis and TNT formation in the tumor-tumor and tumor-astrocyte crosstalk. Our secondary objective is to explore the functional relevance of MB-derived EVs and TNTs for tumor-host tissue interaction and tissue invasion.
We expect this to provide the mechanistic understanding necessary for inspiring the rational design of mechanisms-based therapies targeting tumor-driven deregulation of host tissue functions that contribute to tumor growth and tissue invasion.
Drug discovery: RaSMID
SNF Sinergia Project:
Rational Small Molecule Inhibition of Dissemination (RaSMID) for pediatric brain tumors
The lack of effective therapeutics that allow precise targeting of biological mechanisms promoting tumor progression still hampers the development of anti-metastatic therapies. The targeted disruption of protein-protein interaction (PPI) is an emerging concept in drug discovery, which might help to overcome this bottleneck. If successfully implemented, it offers a highly creative approach towards specific repression or subversion of protein functions under pathological conditions. Elementary prerequisites for the discovery of effective and safe small molecule PPI inhibitors are efficient computational (‘in silico’) screening, functional validation technologies, and physiologically relevant model systems for monitoring biological consequences of compound effects and protein-protein interaction inhibition.
We apply this discovery approach to finding small molecular bioactives against medulloblastoma, the most common malignant pediatric brain tumor. With the expected lead structures targeting dissemination and the establishment of novel methodologies for bioactive compound validation, we hope to markedly contribute to ongoing efforts to provide patients with efficacious and save treatments in the future.
Our collaborators:
Prof. Gisbert Schneider, Computer-assisted Drug Design
Prof. Stephan Neuhauss, Neuhauss Group
The coordinate remodeling of the actin cytoskeleton mediates the motility and invasiveness of cancer cells. It is the interplay of a plethora of signaling pathway components that orchestrates the underlying control of actin cytoskeleton remodeling. We combine pharmacological and genetic gînterference strategies with quantitative imaging tools to identify relevant signaling pathways that promote cell migration and tissue invasion and determine key molecular regulators in these pathways that act as therapy targets for existing drugs or novel compounds.
ONCOGENIC SIGNALING
Molecular signaling pathways control tumor cell behavior and shape the cellular response to anti-cancer therapies. Our research focuses on how pro-oncogenic signals in medulloblastoma cells are initiated, processed, and translated into a biological response. We specifically focus on kinase signaling pathways activated by receptor tyrosine kinases and adhesion receptors, which control actin dynamics, receptor turnover, and cell motility. Our objective is to modulate pro-oncogenic signaling such that the capability of the tumor cells to migrate and invade is repressed.
FGFR signaling promotes growth and tissue invasion in medulloblastoma. We rationally designed and develop a small molecule targeting strategy to block pro-invasive FGFR signaling. We furthermore explore whether novel combinations of existing drugs could enable efficient blockade of pro-metastatic cell functions.
We develop a tissue model for pediatric brain tumor research that allows monitoring of cell behavior, tissue integrity and drug response in real time. Our established organotypic cerebellar slice culture system allows the end-point investigation of molecular mechanisms of tumor growth and tissue invasion and to test novel therapeutic approaches in a physiological environment ex vivo. Our objective is to develop this model further for real-time monitoring of biological responses in a physiologically relevant tissue environment.
Our funding sources: SNF, Swiss Cancer League/Krebsforschung Schweiz, Innosuisse, Kinderkrebsforschung Schweiz
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