[en] Patients with glioblastoma multiforme (GBM) display an overall median survival of 15 months despite multimodal therapy. This catastrophic survival rate is the consequence of systematic relapses which may arise from remaining glioblastoma stem cells (GSC) left behind after surgery. We and others demonstrated that GBM cells enriched in tumor-initiating abilities (or GSC) escape the tumor mass and specifically colonize the adult subventricular zone (SVZ) after transplantation in mice brains. This specific location, away from the initial tumor site, may therefore represent a high-quality model of clinical obstacle to therapy and relapses since GSC specifically retain the ability to form secondary tumors. Relying on recent findings demonstrating the existence of GSC in the human SVZ, we first focused on the molecular mechanisms underlying the oriented migration of these GSC toward the SVZ stem cell niche. In this context, several in vitro experiments strongly suggested the importance of SVZ-released CXCL12 in this original model of brain cancer invasion. Furthermore, interfering with the CXCL12/CXCR4 signalling significantly hampered the in vivo invasion of the SVZ, suggesting this signalling system to tightly regulate GSC migration abilities as well as their particular tropism toward the SVZ region. Then, relying on the implication of GSC in resistance to therapy, we wondered whether the SVZ environment could endorse the role of a GSC reservoir potentially involved in malignant brain tumor relapses. In this context, we demonstrated SVZ-nested GSC to be specifically resistant to radiation in vivo. Interestingly, these cells also displayed enhanced mesenchymal hallmarks compared to GBM cells from the tumor mass. Of note, the acquisition of mesenchymal properties usually correlates with sharper therapeutic resistance. These mesenchymal traits were further shown up-regulated upon CXCL12 stimulation in vitro. Interestingly enough, SVZ-released CXCL12 was finally demonstrated to mediate GBM resistance to radiation in vitro. Taken together, these data highlighted the critical role undertaken by CXCL12 in mediating the invasion of the SVZ environment by GBM cells enriched in tumor-initiating abilities (GSC). These findings also underpinned the adult SVZ stem cell niche as a potential environment involved in GBM extrinsic resistance to radiotherapy and strongly suggest the SVZ to play a role in GBM relapses. Further research is therefore mandatory to better characterize the relationship between GSC and the SVZ. This could potentially lead to the identification of new therapeutic targets disrupting this union and impairing with GSC intrinsic properties.
