Targeting Self-Renewal in High-Grade Brain Tumors Leads to Loss of Brain Tumor Stem Cells and Prolonged Survival

Cancer stem cells (CSCs) have been suggested as potential therapeutic targets for treating malignant tumors, but the in vivo supporting evidence is still missing. Using a GFP reporter driven by the promoter of the nuclear receptor tailless (Tlx), we demonstrate that Tlx+ cells in primary brain tumors are mostly quiescent. Lineage tracing demonstrates that single Tlx+ cells can self-renew and generate Tlx− 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 and prolongation of animal survival, accompanied by induction of essential signaling pathways mediating cell-cycle arrest, cell death, and neural differentiation. Our study demonstrates the feasibility of targeting glioblastomas and indicates the suitability of BTSCs as therapeutic targets, thereby supporting the CSC hypothesis. [Display omitted] •A mouse brain tumor model for tumor stem cell-specific gene targeting is presented•Tlx is only expressed in brain tumor stem cells of mouse primary gliomas in vivo•BTSC-specific knock-out of Tlx leads to the loss of BTSCs and prolonged survival•Loss of BTSCs leads to cell death, cell-cycle arrest, and differentiation Zhu et al. demonstrate that cells expressing the neural stem cell marker Tlx in glioblastoma are largely quiescent, but can self-renew to generate Tlx− tumors. Inducibly targeting TLx in Nestin-expressing brain tumor cells results in cell death, cell-cycle arrest, and neural differentiation.