Genetics of invasive, human glioma stem cells isolated "ex vivo" and the role of SOX2 and HEY1 signalling.
Research Project
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01.06.2009
- 31.05.2012
Gliomas are among the deadliest malignancies, against which conventional therapies have not significantly improved patient survival. Indeed, glioma cells are extremely resistant to chemo/radiotherapy, and tumor invasion into adjacent brain tissue renders complete resection by surgery impossible. In fact, invasiveness is a hallmark of all known molecular subsets of glioma WHO grade II-IV and can considerably vary from one tumor to another, regardless of the tumor molecular subset. This invasive phenotype can be estimated by magnetic resonance imaging and histopathological analysis. In order to identify molecular mechanisms of glioma invasion, we previously performed RNA micro-array analyses of highly invasive vs poorly invasive WHO grade II gliomas. Through this strategy, we identified genes that are differentially expressed between both invasive behaviors. Among them are those encoding transcription factors SOX2 and HEY1. We plan: first, to further investigate a possible cause-and-effect relationship between SOX2 and HEY1 (in)activation on cell motility and invasion; and second, to identify their target genes by using micro-arrays for gene expression profiling and for genome-wide transcription factor/DNA interaction by chromatin immunoprecipitation. Furthermore, we plan a more sophisticated strategy of identifying invasion-associated genes by comparing RNA expression signatures of glioma cells from invasive vs non-invasive areas within the same tumor. Candidate genes will be validated through the same process as for SOX2 and HEY1. Results should provide clues on the molecular mechanisms of glioma invasion into adjacent brain tissue. Moreover, at the clinical point of view, identified genes would designate potential targets for customized therapies to control glioma invasion.
