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Role of differentiation in glioblastoma invasion

PhD ceremony:Mr J. (Justin) Vareecal Joseph
When:May 11, 2015
Supervisor:prof. dr. F.A.E. (Frank) Kruyt
Co-supervisor:dr. W.F.A. (Wilfred) den Dunnen
Where:Academy building RUG
Faculty:Medical Sciences / UMCG
Role of differentiation in glioblastoma invasion

Glioblastoma (GBM) is the most aggressive brain tumour and its diffuse infiltration into normal brain tissue is one of the main causes for poor prognosis, making complete surgical removal virtually impossible. The main aim of the research described in this thesis was to investigate the possible involvement of differentiation of GBM cells in the invasive behaviour of GBM. First, we discovered that two important micro environmental factors in GBM, i.e. TGF-β and hypoxia, induced a mesenchymal trans-differentiation in GBM cells thereby enhancing its invasive potential. The transcription factor ZEB1 was identified as a critical regulator of this process. Second, the involvement of the differentiation state in GBM in determining their invasive capacity was examined. Interestingly, differentiated GBM cells appeared more invasive than the undifferentiated GBM (stem) cells. Further, we showed that differentiated cells could also revert back and gain many of the properties associated with stem cells, hence sustaining tumourigenicity. These novel findings indicate that mesenchymal transition and differentiation enhance the invasive capacity of GBM cells. Inhibition of the identified pathways contribute to heterogeneity and provide potential therapeutic targets to reduce the infiltrating behaviour of this aggressive and lethal brain tumour.