Abstract 168: Genomic heterogeneity drives distinct infiltration patterns in glioblastoma

Abstract Glioblastoma is the most common and malignant type of primary brain cancer with a median patient survival of only 15 months. Tumors are typically categorized into three molecular subtypes—proneural, classical, and mesenchymal—each linked to specific genomic and microenvironmental factors. However, the functional and clinical implications of these subtypes remain poorly understood. Standard treatment involves surgical resection followed by chemotherapy and radiotherapy. Despite this, malignant cells have already at the time point of diagnosis infiltrated healthy brain tissue, driving tumor recurrence. Infiltrating cells have been found to maintain high proliferative rates while invading the brain (termed “go-and-grow”) but have also been shown be non-proliferative (termed “go-or-grow”). Here, we perform computational analyses on transcriptomic data from over 600 patients, supplemented with genomic data, to investigate infiltration patterns in glioblastoma tumors. We identify a proliferative astrocytic state strongly associated with the classical subtype and EGFR amplification and distinct from a non-proliferative astrocytic state. Further analysis showed subtype-specific infiltrative patterns between the tumor core and adjacent brain tissue. To validate these findings, we performed single-cell spatial transcriptomics on patient samples, revealing that classical tumors exhibit a “go-or-grow” phenotype, where core regions are proliferative and infiltrative regions are dormant. In contrast, proneural tumors maintain consistent malignant states and proliferation rates, reflecting a “go-and-grow” phenotype. These findings indicate a direct relationship between the genomic status of glioblastoma tumors and the transcriptomic profiles of their infiltrating malignant cells. Together, our study provides insights into genomically-driven infiltration patterns in proneural and classical glioblastomas, with potential implications for clinical treatment. Citation Format: Dylan Harwood, Sara Blaabjerg Artzi, Vilde Pedersen, Alessio Locallo, Maya Jeje Lü, David Scheie, Anne Dorte Nørøxe, Nadine Margaretha Hammouda, Ulrik Lassen, Joachim Lütken Weischenfeldt, Bjarne Winther Kristensen. Genomic heterogeneity drives distinct infiltration patterns in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 168.