Periostin Safeguards EGFR‐Driven Genomic Instability and Sustains the Immune‐Suppressive Niche in Glioblastoma

Glioblastoma (GBM) heterogeneity limits the efficacy of EGFR‐targeted therapies. Here, we present a spatially stratified single‐cell atlas of IDH‐wildtype GBM to dissect the impact of EGFR amplification on tumor architecture. We demonstrate that EGFR amplification disrupts the spatial coupling between evolutionary state and anatomical location, resulting in premature acquisition of invasive phenotypes—a phenomenon we term “accelerated evolutionary velocity.” Unlike nonamplified tumors which maintain a strict “Core‐to‐Margin” developmental gradient, malignant cells in EGFR‐amplified tumors acquire invasive mesenchymal traits preemptively regardless of their spatial niche. This accelerated evolution parallels the Core behaving as a “genotoxic stress reservoir” characterized by elevated chromosomal instability (CIN) ( p < 2.2 × 10 −16 ). This genotoxic stress coincides with the emergence of a localized tumor–myeloid axis and an immune‐suppressive niche. Using the PriorityScore2 framework, we prioritized Periostin (POSTN) as a top‐tier clinically relevant candidate. In the high‐CIN environment of EGFR‐amplified GBM, in silico network perturbation suggested that POSTN may function as a candidate modulator of mitotic fidelity, potentially buffering against lethal genomic instability while sustaining rapid clonal evolution. Validated across multicenter cohorts, POSTN showed robust upregulation, strong diagnostic performance (AUC = 0.961), and significant prognostic relevance, emerging as a potential therapeutic vulnerability linking accelerated evolution with immune privilege in the GBM ecosystem.