RT Journal Article SR Electronic T1 Vulnerability of invasive glioma cells to lysosomal membrane instabilization JF bioRxiv FD Cold Spring Harbor Laboratory SP 276402 DO 10.1101/276402 A1 Joncour, Vadim Le A1 Hyvönen, Maija A1 Filppu, Pauliina A1 Turunen, Pauliina S. A1 Sihto, Harri A1 Burghardt, Isabel A1 Joensuu, Heikki A1 Tynninen, Olli A1 Jääskeläinen, Juha A1 Weller, Michael A1 Lehti, Kaisa A1 Laakkonen, Pirjo YR 2018 UL http://biorxiv.org/content/early/2018/03/05/276402.abstract AB Diffusive by nature, glioma challenges clinical care by the impossibility of complete surgical resection of tumor, leaving the radio- and chemoresistant cells responsible for recurrence intact. We identified mammary-derived growth inhibitor (MDGI/FABP3) as invasive glioma biomarker. Here, we show that high MDGI expression associated with poor patient survival and promoted invasive glioma cell growth both in vitro and in vivo, while MDGI silencing drastically compromised patient-derived tumoroid viability via induction of lysosomal membrane permeabilization (LMP). This alternative cell death pathway provokes release of lysosomal hydrolases into the cytosol leading inevitably to the cell death. Our results show a novel functional role for MDGI in glioma cell invasion, survival, and maintenance of the lysosomal membrane integrity as well as an unsuspected sensitivity of glioma cells to an LMP-inducing drug, anti-histamine clemastine. In a preclinical study, clemastine-treatment significantly prolonged the survival of intracranial glioblastoma-bearing animals due to eradication of invasive glioma cells. This glioma cell vulnerability to LMP-inducing drugs opens new horizons for development of novel treatments and suggest re-positioning of an established drug for new indication.