ID #421 Copper deprivation disrupts epigenetic, kinase, and metabolic signaling to induce DNA damage and mitotic failure in Diffuse Midline Glioma

Abstract

Diffuse Midline Gliomas (DMG) are fatal pediatric brain tumors driven by H3K27M alterations and characterized by dysregulated metabolism and kinase signaling. Because copper accumulation modulates these pathways in neuropathies and cancer, we investigated its role in DMG pathogenesis. Transcriptomic analysis of patient samples revealed elevated expression of the copper-chaperone metallothionein 1X (MT1X), while mass-spectrophotometric imaging (ICP-MS) confirmed copper accumulation in DMG cell lines, patient-derived xenograft (PDX) models, and autopsy tumors compared with non-tumor brains. H3K27M-altered cells displayed increased copper transporter 1 (CTR1) and heightened sensitivity to the copper-chelating agent tetraethylenepentamine (TEPA). Multi-omic analyses showed TEPA suppressed PI3K/AKT and MAPK signaling, impaired G2–M kinase and metabolic networks, altered epigenetic regulators, and induced DNA damage and mitotic failure. Copper supplementation or metabolic rescue restored kinase activity and viability, confirming copper dependency. In orthotopic PDX models, oral TEPA crossed the blood–brain barrier, reduced brain copper, and significantly extended survival without toxicity. These findings identify copper as a master regulator of metabolic, kinase, and epigenetic signaling in H3K27M-DMG and support copper deprivation as a safe, repurposable targeted therapy to induce mitotic failure in aggressive pediatric brain tumors.