MDB-34. “INDUCING IRON IMBALANCE BY TARGETING THE ABCB7/GPX4 AXIS ACCELERATES FERROPTOSIS IN MEDULLOBLASTOMA”

Abstract Medulloblastomas (MB), the most common malignant pediatric brain tumor and a leading cause of childhood mortality, are stratified into four primary subgroups. Deletions within chromosomal locus 17p13.3, which houses multiple suppressor genes including miR-1253, characterize high-risk group 3 tumors. These aggressive tumors also enrich iron transport to satisfy their high proliferative need. MiR-1253 targets by inhibiting mitochondrial Fe-S transporter, ABCB7. This study elucidated impact repressing ABCB7 on cisplatin cytotoxicity in MB whether these effects were mediated ferroptosis. In silico vitro analyses revealed specific enrichment GPX4, critical regulator ferroptosis, cell lines overexpression (miR-1253OE) resulted downregulation both concurrently increasing overload, oxidative stress, lipid peroxidation, death abrogation medullosphere formation; knockdown (ABCB7KD) recapitulated abrogated GPX4 expression. Fractionation studies confirmed inhibitory miR-1253OE ABCB7KD expression cytosol mitochondria. Seahorse that bulk ATP generation was occurring cytoplasm through glycolysis not via phosphorylation, suggesting dysfunction triggered when repressed. Cisplatin, chemotherapeutic agent used treatment, induces DNA crosslinking; it inhibits cancer cells, IC50 reduced 2-fold. Resultantly, treatment augmented stress depleted glutathione stores, culminated higher index mouse model tumors, potentiated dramatically prolonged survival. The current illustrates how targeting can augment ferroptosis potentiate