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Vulnerability of invasive glioma cells to lysosomal membrane instabilization

Vadim Le Joncour, Maija Hyvönen, Pauliina Filppu, Pauliina S. Turunen, Harri Sihto, Isabel Burghardt, Heikki Joensuu, Olli Tynninen, Juha Jääskeläinen, Michael Weller, Kaisa Lehti, View ORCID ProfilePirjo Laakkonen
doi: https://doi.org/10.1101/276402
Vadim Le Joncour
1Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, 00290, Finland
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Maija Hyvönen
1Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, 00290, Finland
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Pauliina Filppu
1Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, 00290, Finland
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Pauliina S. Turunen
2Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki, 00290, Finland
3Department of Microbiology, Tumor and Cell Biology (MTC) Karolinska Institutet, SE-17177 Stockholm, Sweden
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Harri Sihto
1Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, 00290, Finland
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Isabel Burghardt
4Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, 8091, Switzerland
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Heikki Joensuu
1Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, 00290, Finland
5Department of Oncology, Helsinki University Hospital, Helsinki, 00029, Finland
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Olli Tynninen
6Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, 00014, Finland
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Juha Jääskeläinen
7Kuopio University Hospital, Kuopio, 70210, Finland
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Michael Weller
4Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, 8091, Switzerland
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Kaisa Lehti
2Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki, 00290, Finland
3Department of Microbiology, Tumor and Cell Biology (MTC) Karolinska Institutet, SE-17177 Stockholm, Sweden
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Pirjo Laakkonen
1Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, 00290, Finland
8Laboratory Animal Centre, University of Helsinki, Finland
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  • ORCID record for Pirjo Laakkonen
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Abstract

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.

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Posted March 05, 2018.
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Vulnerability of invasive glioma cells to lysosomal membrane instabilization
Vadim Le Joncour, Maija Hyvönen, Pauliina Filppu, Pauliina S. Turunen, Harri Sihto, Isabel Burghardt, Heikki Joensuu, Olli Tynninen, Juha Jääskeläinen, Michael Weller, Kaisa Lehti, Pirjo Laakkonen
bioRxiv 276402; doi: https://doi.org/10.1101/276402
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Vulnerability of invasive glioma cells to lysosomal membrane instabilization
Vadim Le Joncour, Maija Hyvönen, Pauliina Filppu, Pauliina S. Turunen, Harri Sihto, Isabel Burghardt, Heikki Joensuu, Olli Tynninen, Juha Jääskeläinen, Michael Weller, Kaisa Lehti, Pirjo Laakkonen
bioRxiv 276402; doi: https://doi.org/10.1101/276402

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