Distant origin of glioblastoma recurrence: neural stem cells in the subventricular zone serve as a source of tumor reconstruction after primary resection

Abstract

Glioblastoma (GBM) is the most aggressive and common type of primary malignant brain cancer in adults. GBM often recurs locally near the resection cavity (RC) following the surgical removal of primary tumors. Recent research has reported that neural stem cells (NSCs) in the subventricular zone (SVZ) harboring cancer-driving mutations serve as the cells of origin for human GBM. However, the pathological role of tumor-initiating NSCs in the SVZ in tumor recurrence remains to be elucidated. Here, we explore the potential contribution of mutation-harboring NSCs in the SVZ to tumor recurrence around the RC following surgical resection. Our hypothesis emerged from performing deep sequencing of longitudinal tissues from 10 patients with GBM, including (i) tumor-free SVZ tissue, (ii) primary tumor tissue, (iii) recurrent tumor tissue, and (iv) blood. As a result of this sequencing, we observed evidence suggesting that recurrent tumors show genetic links to the SVZ in 60% (6/10) of patients, which are distinct from the primary tumors. Using a genome-edited mouse model, we further identified that mutation-harboring NSCs appeared to migrate to the RC through the aberrant growth of oligodendrocyte progenitor cells, potentially contributing to the reconstruction of high-grade malignant gliomas in the RC. This process was associated with the CXCR4/CXCL12 axis, as supported by RNA sequencing data from human recurrent GBM. Taken together, our findings suggest that NSCs in human SVZ tissue may play a role in GBM recurrence, potentially highlighting a novel distant contributor of recurrence.