ERO1a fosters glioblastoma aggressiveness and metabolic flexibility by regulating mitochondria-associated membrane dynamics

: Despite the wealth of data generated in the omics era to investigate molecular drivers, glioblastoma (GBM) remains one of the most incurable cancers with a poor median of survival. Here we unravelled the dynamic crosstalk between the endoplasmic reticulum and mitochondria, known as mitochondria-associated membranes (MAMs) and define how modulation of calcium fluxes and MAM structure influences GBM cell plasticity and metabolic flexibility. We identified ERO1α, whose expression is significantly associated with poor GBM patient survival, as a critical MAM protein that regulates MAM structure, dynamics and calcium-mediated functions. Our data demonstrate that ERO1α activity and expression promotes GBM aggressiveness in vitro and in vivo and enhances mitochondrial oxidative phosphorylation. By establishing a direct link between ERO1α-mediated MAM modulation and the antitumour effects of ERO1α inhibition, this work highlights a context-dependent, druggable vulnerability that can be exploited for GBM therapy.