Wed, 19/03/2014 - 10:00
,
Campus Homburg, Geb. 60, HS Humangenetik

Dr Hai-Kun Liu
(
Host: Dr. Bin Qu & Prof. Dr. Markus Hoth
)
German Cancer Research Center (DKFZ) Heidelberg

Targeting brain tumor stem cells in mouse model

Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still limited. I will present a mouse model that allows stem cell-specific gene targeting in unperturbed high-grade mouse brain tumors. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), a neural stem cell (NSC)-specific transcription factor, we found that Tlx-positive cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx-positive cells can self-renew and generate Tlx negative tumor cells in primary tumors, suggesting that they are brain tumor stem cells (BTSCs). After introducing a BTSC-specific knock-out of the Tlx gene in primary mouse tumors, we observed a loss of self-renewal of BTSCs, which leads to a significant prolongation of animal survival. Furthermore, we demonstrate that loss of Tlx in BTSCs leads to the induction of essential signaling pathways mediating cell cycle arrest, cell death and neural differentiation. Additionally we show that Tlx serve as a novel prognostic marker in human high-grade brain tumors indicating reduced survival. Our study provides a novel therapeutic target of targeting glioblastomas and demonstrates that BTSCs are suitable therapeutic targets, thus strongly supporting the CSC hypothesis and the importance of therapeutic approaches targeting self-renewal pathway.

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