Abstract
Glioblastomas (GBM) are characterized as highly malignant brain tumours, hallmarked by infiltrating tumour cells. Their pathogenesis may depend on Brain Tumour Initiating Cells (BTIC), according to recent publications. The subventricular zone and hippocampus are areas where BTICs may arise and migrate to distinct areas to initiate a tumour bulk via differentiation into the glial linage. In consequence, it is relevant to investigate the transdifferentiation, migratory and invasive potential of BTICs through the identification of molecules and pathways controlling the induction of invasion. Therefore, this study aimed to identify characteristics specific for invasion-driving GBM cells. Invasion of GBM cells was induced in an in situ model of organotypic brain slice cultures (OBSC), a valuable tool to visualize and analyse migration and invasion in a setting that simulates normal brain tissue conditions. Fluorescence tagged BTICs were inoculated in the hippocampal region of fresh brain slice cultures from new-born rats to monitor tumour cell invasion for three weeks. During this time, invasive cells emerge from the initial cell population, driving invasion into the surrounding tissue. Those invasive cells differ in morphology and behaviour from stationary cells remaining at the implantation site. An adapter was constructed to fit to a micromanipulator to isolate the different cell subpopulations from the OBSC. After cDNA library generation and subsequent microarray analysis, a detailed comparison has been made between both groups to compare gene expression profiles of genes associated with e.g. proliferation, invasion, cell-cell contacts, and stemness. Here, invasive cells showed a markedly distinct expression pattern in comparison to stationary cells. Identified transcription factors and their target gene expression will be verified in different BTIC subsets. Overall expressed genes specific for leader cells will be further characterized and regulated to manipulate the invasive behaviour and tumourigenicity of BTICs.
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