Abstract B038: Investigating the impact of the aged brain environment on glioblastoma progression

Abstract Glioblastoma is the most common primary malignant brain tumor in adults. Despite surgical resection followed by chemo- and radiotherapy, this cancer remains incurable, with most patients succumbing to the disease within two years of diagnosis. Age is a major risk factor for glioblastoma, with patients over 65 experiencing more aggressive disease and reduced survival. However, limited transcriptional and mutational differences have been identified between resected tumors from young and old patients. This suggests that components of the aged brain environment, beyond the tumor bulk, may contribute to disease progression in older individuals. Recent studies focused on normal aging have revealed that the white matter and vasculature become increasingly inflamed with age. These structures play a crucial role in glioblastoma growth and invasion, but the role of age-associated changes in the brain on tumor growth remains poorly understood. Further understanding of how the aged brain impacts tumor growth may uncover why older patients have worsened prognosis and identify pathways that can be targeted to slow tumor progression. To address this, we intracranially injected murine GL261 glioblastoma cells into immune competent mice of varying ages. We found that tumors grew significantly faster in aged mice (>12-months-old) than young mice (3-months-old), with single-nucleus RNA-sequencing revealing pronounced transcriptional changes across multiple cell types in the aged tumor-bearing brain. To better understand how age-associated changes in the cellular architecture of the brain influence tumor cell behavior, we performed in situ hybridization-based spatial transcriptomics using a custom 480-gene panel comprised of brain cell markers, tumor cell states, and brain aging signatures. Using graph-based spatial biology approaches, we resolved cells and brain regions and compared the spatially informed transcriptional changes in each cell type across age groups. We found increased inflammation-related gene expression signatures throughout the aged tumor-bearing brain, with especially pronounced changes observed in aged oligodendrocytes in the white-matter tracts. Interestingly, these age-associated differences were less pronounced within the tumor bulk and tumor-proximal brain, consistent with findings from human patient data. Together, these results suggest that age-associated changes in the brain manifesting outside of the tumor bulk underlie worse outcomes in aged individuals. Further investigations into these interactions will elucidate their role on tumor cell invasion and proliferation. These age-associated signatures may be amenable to targeting during early stages of tumor development, enabling more proactive treatment approaches to extend survival for older glioblastoma patients. Citation Format: Megan Callender, Jennifer Sargent, Muneer Hasham, Anne Marchini, Elaine Bechtel, David Coleman, Derek Wainwright, Frederick S. Varn. Investigating the impact of the aged brain environment on glioblastoma progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B038.