Speaker
Description
Glioblastoma multiforme (GBM), the most aggressive brain tumor, interacts with its tumor microenvironment (TME) through complex mechanisms. GBM-TME interactions are primary drivers of tumor malignancy and progression. The TME consists of the extracellular matrix (ECM) and various cells of the brain. Novel research strategies to expand on the understanding of these interactions as a prerequisite to develop new therapeutic avenues are imperative for this tumor type.
We have previously established a triculture system that includes glioma cells, neurons and astrocytes using an ultra-soft hyaluronic acid-based (HA-SH) hydrogel. We found that native molecular mechanisms described for glioma cells in vivo were recapitulated in the 3D composite; including direct cell-cell interactions between glioma cells and neurons or astrocytes. Moreover, the system provided a brain-like ECM that allowed the functional maturation of a neuronal network. In the presence of glioma cells, the neuronal network had a hyperexcitable phenotype with increased firing rates and synchronicity. The developed platform proved to be a viable option for the study of complex systems and interactions for GBM-TME models.
Here, a modified version of the previous hydrogel supplemented with collagen type IV, laminin and fibronectin is utilized to improve mimicry of the brain ECM. In this modified hydrogel, ANG (astrocytes-neurons-glioma) tri- and MANG (microglia-astrocytes-neurons-glioma) tetraspheroids are embedded to investigate the role of microglia-glioma interactions in a high-cell density configuration. Microglia cells are part of the innate immune response representing the primary line of defense against external agents of the central nervous system . Beyond their immune system function it has been extensively shown that microglia cells are involved in processes to maintain proper neuronal function. Microglia cells have been demonstrated to directly interact with glioma cells thus we want to analyze in MANG spheroids. Furthermore, we aim to investigate the functional impact of microglia on the primary neurons. As shown in the figure, in the presence of microglia cells in the MANG spheroid configuration, neurons generate spontaneous and robust calcium transients. With an assessment of neuronal calcium transients in ANG and MANG spheroids together with the expression profile, we seek to recapitulate and understand the role of the immune milieu of GBM in a high-throughput 3D composite system. Increasing the complexity of the basic building blocks of our previously developed system, for both ECM and cell types, we take a step towards reproducing the complex TME of GBM in an in vitro model.
32028928446