Abstract 5666: Exploring spatially resolved intra-tumoral heterogeneity of glioblastoma and neuronal mechanisms facilitating brain invasion

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Abstract Glioblastoma (GBM) is a highly lethal brain cancer, comprising about half of all central nervous system malignancies. Its recurrence and resistance to aggressive treatments, such as surgery, radiation, and chemotherapy, underscore its biological complexity. A key feature of GBM is intra-tumoral heterogeneity (ITH), stemming from a diversity of transcriptional cell states within the tumor. While genetic contributions to ITH are well-researched, the role of non-genetic factors, especially in promoting transitions between the various transcriptional cell states (referred to as plasticity), is less understood. This plasticity enables GBM cells to survive treatment pressures, necessitating a deeper dive into the epigenetic underpinnings that govern it and the role of the tumor microenvironment (TME) in influencing it. We proposed that the TME significantly impacts the epigenetic landscape of both malignant and surrounding non-malignant cells, thereby promoting ITH and cell state plasticity. To assess this, we analyzed samples from different anatomical areas of GBM tumors collected using MRI-guided selection. Utilizing advanced multimodal single-cell sequencing technologies, we profiled the transcriptomes and epigenomes of individual cells, revealing their spatially dependent phenotypic and epigenetic diversity. Our results indicated a higher enrichment of progenitor-like malignant cells, resembling neural or oligodendrocyte progenitors, around the tumor margins. In contrast, the core mainly contained differentiated cells with mesenchymal-like characteristics. Intriguingly, progenitor-like cells in the peri-tumoral zone expressed a unique neuronal activity program, including elevated levels of PRC2 complex targets, which are critical for maintaining the pluripotency and self-renewal capabilities of neural stem cells. Additionally, our analysis of cell-cell interactions between neurons and malignant cells identified ligand-receptor pairs crucial for axon guidance, neurogenesis, and tumor invasion. Proneural factors, critical for neural differentiation, were more accessible in peri-tumoral progenitor-like cells, suggesting that malignant cells might exploit neurodevelopmental routes for growth and invasion. This work underscores the significant spatial cellular heterogeneity of GBM and the variation in epigenetic states across the tumor, demonstrating how GBM cells can hijack neurodevelopmental pathways to foster invasion. Although surgical resection can target the tumor core, our insights into the invasive mechanisms of malignant cells provide a foundation for developing targeted therapies to combat the highly invasive cells persisting in regions adjacent to the tumor. Citation Format: Federico Gaiti, Yiyan Wu, Sheila Mansouri, Benson Wu, Yosef Ellenbogen, Xuyao Li, Parnian Habibi, Joan Kant, Pathum Kossinna, Sandra Ruth Lau Rodriguez, Gelareh Zadeh. Exploring spatially resolved intra-tumoral heterogeneity of glioblastoma and neuronal mechanisms facilitating brain invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5666.