Abstract
Glioblastoma (GBM), the most common malignant primary brain tumor in adults, has a median survival of 15 months and 5-year survival rate of only 6.9%. Standard of care, including radiation and chemotherapy, can induce cellular senescence in the brain. The senescence-associated secretory phenotype (SASP) significantly affects glioma microenvironment as these secreted factors exhibit both anti-and pro-tumorigenic effects. However, it is currently unknown whether senescence in the surrounding GBM microenvironment could be beneficial or detrimental to tumor outcomes. Using cell-specific proteomics, we identified upregulation of cathepsin B (CTSB) expression in patient-derived brain tumor initiating cells (BTICs) co-cultured with human fetal neural progenitor cells (NPCs). In matched patient tumor biopsies, sequencing of lateral ventricle (LV)-proximal regions revealed increased CTSB expression compared to LV-distal counterparts. Remarkably, LV-proximal GBMs induced a senescent phenotype and reduced differentiation in subventricular zone (SVZ) NPCs through CTSB secretion. We hypothesize that senescent NPCs in the SVZ contribute to a pro-tumorigenic microenvironment that promotes tumor aggressiveness in LV-proximal GBM. To model this in vitro, senescence was induced in NPCs using recombinant CTSB (100 nM) and hydrogen peroxide (250 µM, 2 hours). Treated NPCs showed increased β-galactosidase activity and increased expression of SASP factors IL-1α, IL-6, and CTSB. Senescent NPCs significantly increased BTIC migration and proliferation (p<0.05) both in co-culture and through conditioned media, suggesting this effect may be mediated by soluble factors. These findings support the hypothesis that senescent NPCs promote BTIC malignancy in LV-proximal GBM and identify CTSB as a potential mediator of this interaction.