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Abstract
Tumor cells manipulate the surrounding tumor microenvironment (TME) to sustain their growth and progression. Here, we demonstrate that H3 K27-altered diffuse midline gliomas (DMG-H3K27a) modulate microglial polarization, leading to the secretion of heparin-binding EGF-like growth factor (HBEGF). This paracrine signaling cascade activates oncogenic epidermal growth factor receptor (EGFR) signaling in tumor cells, driving DMG-H3K27a proliferation and tumor expansion. HBEGF neutralization effectively disrupted the microenvironment-driven proliferation of DMG-H3K27a cells, revealing a critical dependency on paracrine signaling for tumor growth. Pharmacological inhibition of EGFR effectively suppresses tumor cell growth, while genetic targeting of EGFR further impairs disease progression in vivo. These findings highlight a TME-mediated oncogenic mechanism and suggest potential therapeutic strategies for pediatric high-grade gliomas.