Abstract 904: 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

Abstract Glioblastoma multiforme (GBM) is the most common lethal primary brain tumor. Neural stem cells (NSCs) harboring cancer-driving mutations in the subventricular zone (SVZ) have recently been reported as the cells of origin for human glioblastoma (GBM) through migration. However, the pathological role of residual tumor-initiating NSCs (tNSCs) in the SVZ is undetermined for local recurrent tumor 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, we hypothesized that, after complete removal of the primary tumor, the tNSCs in SVZ might be the source for tumor construction at RC. Here, we examined the role of tNSCs in the development of local tumors around RC using a mouse model and genetic analysis of 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 stereotaxic 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, we performed deep sequencing of longitudinal matched tissues consisting of (i) normal SVZ away from the tumor, (ii) primary tumor, (iii) recurrent tumor, and (iv) blood in the patients with GBM, IDH wildtype. We found that the dominant clones of recurrent tumors genetically arose from the SVZ, not directly from the primary tumor. Third, the CXCR4/CXCL12 axis was upregulated through migration from the SVZ and tumor formation at the RC compared with primary tumors without the RC in mouse models. Blockage of the CXCR4/CXCL12 axis decreased the number of immigrating OPC lineage cells specifically and improved tumor control and survival rates. 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 the main local failures after resection. Citation Format: Xue Li, Hyun Jung Kim, Jeong Ho Lee, Hong-Gyun Wu, Joo Ho Lee. 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]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 904.