PT  - JOURNAL ARTICLE
AU  - Vadim Le Joncour
AU  - Maija Hyvönen
AU  - Pauliina Filppu
AU  - Pauliina S. Turunen
AU  - Harri Sihto
AU  - Isabel Burghardt
AU  - Heikki Joensuu
AU  - Olli Tynninen
AU  - Juha Jääskeläinen
AU  - Michael Weller
AU  - Kaisa Lehti
AU  - Pirjo Laakkonen
TI  - Vulnerability of invasive glioma cells to lysosomal membrane instabilization
AID  - 10.1101/276402
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 276402
4099  - http://biorxiv.org/content/early/2018/03/05/276402.short
4100  - http://biorxiv.org/content/early/2018/03/05/276402.full
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.