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Glioblastoma (GB) remains one of the most aggressive and lethal brain cancers, characterized by profound heterogeneity and resistance to standard therapies. The current treatment regimen with surgical resection and chemoradiotherapy is not curative and GB will almost always recur in proximity to the resection cavity. This thesis explores the molecular and phenotypic complexity of GB through a series of investigations that utilize advanced multiomic approaches to explore the interplay between epigenetic regulation, lineage specificity, and tumor microenvironment interactions.

Paper I employs single-nucleus RNA sequencing, ATAC sequencing, and whole exome sequencing to compare the central tumor mass with the invasive edge in GB patients revealing that peritumoral cells exhibit distinct phenotypes marked by increased invasiveness, immune activation, and mesenchymal-like states while showing reduced proliferative capacity. These cells possess fewer genetic alterations but undergo significant epigenetic reprogramming, suggesting that targeting the immune-driven epigenetic changes could be a promising therapeutic strategy to prevent tumor recurrence.

Paper II investigates the influence of TP53 mutational status on epigenetic regulation in GB. Two epigenetically distinct subgroups—ATAC-C2 and ATAC-C3—were identified, correlating with divergent survival outcomes. ATAC-C2 tumors, linked to disruptive TP53 mutations, exhibit a mesenchymal, immune-activated phenotype and resistance to standard therapy. In contrast, ATAC-C3 tumors, which retain functional p53 activity, demonstrate better therapeutic responsiveness. This underscores the therapeutic potential of targeting mutation-specific p53 reactivation and alternative agents to counteract resistance mechanisms.

Paper III focuses on enhancer signatures and their role in defining GB subgroups with divergent survival rates. By integrating ATAC-seq and CUT&Tag data, we identify distinct enhancer landscapes that drive mesenchymal-like and neural progenitor-like phenotypes in ATAC-C2 and ATAC-C3 subgroups, respectively. The results highlight that enhancer signatures are more predictive of patient prognosis than traditional transcriptome-based subtyping. Furthermore, the findings reveal lineage-specific transcription factor networks that shape each subgroup's aggressiveness and therapeutic response, paving the way for novel epigenetic therapeutic strategies.

Together, these papers contribute to a deeper understanding of GB biology by elucidating the epigenetic mechanisms underlying tumor heterogeneity, invasion, recurrence, and resistance. They highlight the significance of personalized therapeutic approaches tailored to the unique molecular landscapes of GB subgroups, emphasizing the potential of targeting immune-activated states, TP53 vulnerabilities, and enhancer-driven transcriptional programs.