STEM-09. NEURAL STEM CELLS OF THE SUBVENTRICULAR ZONE EVOLVE INTO TUMORS AROUND THE RESECTION CAVITY AFTER SURGICAL RESECTION OF GLIOBLASTOMA VIA THE CXCL12/CXCR4 AXIS

Abstract

Listen

Translate article

Abstract Neural stem cells (NSCs) harboring cancer-driving mutations in the subventricular zone (SVZ) have recently been reported as the cells of origin for human GBM. However, the pathological role of residual tumor-initiating NSCs (tNSCs) in the SVZ is undetermined for recurrent tumors after surgical removal of the primary tumor. After the primary resection of GBM, most recurrences still appear as local tumors around the resection cavity (RC). Accordingly, after surgical removal, we hypothesized that the tNSCs in SVZ might be the source for tumor construction at RC as local recurrence. Here, we examined the role of tNSCs in developing local tumors around RC using a mouse model and human tissues. First, cancer-driving mutations, including Trp53, Pten, and Egfr mutations, were introduced to NSCs in SVZ through in vivo electroporation, and the RC was generated in the remote cortex through surgical resection. We found that the NSCs harboring driver mutations migrated specifically to the RC through the aberrant growth of oligodendrocyte-precursor cells (OPCs). Furthermore, the SVZ-originated cells constituted the GBM around the RC at four weeks post-resection in 64% of mouse models. Second, the CXCR4/CXCL12 axis was upregulated through migration from the SVZ and tumor formation at the RC compared with primary tumors without the RC. Blockage of the CXCR4/CXCL12 axis decreased the number of immigrating OPC lineage and switched the differentiation of tNSC to astrocyte lineage. Furthermore, it improved survival rates in vivo. Third, we validated the independent clonal evolution of recurrent tumor from SVZ and the upregulation of CXCR4 axis in the recurrent tumor in a human patient. Taken together, our results reveal that the residual tNCSs harboring cancer-driving mutations in the SVZ can re-construct tumors after surgical resection of GBM. Blocking CXCL12/CXCR4 might be a potential treatment strategy for preventing recurrences after resection.