Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization
Abstract The current clinical care of glioblastomas leaves behind invasive, radio‐ and chemo‐resistant cells. We recently identified mammary‐derived growth inhibitor (MDGI/FABP3) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membr...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2019-06-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809034 |
| _version_ | 1797281970623873024 |
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| author | Vadim Le Joncour Pauliina Filppu Maija Hyvönen Minna Holopainen S Pauliina Turunen Harri Sihto Isabel Burghardt Heikki Joensuu Olli Tynninen Juha Jääskeläinen Michael Weller Kaisa Lehti Reijo Käkelä Pirjo Laakkonen |
| author_facet | Vadim Le Joncour Pauliina Filppu Maija Hyvönen Minna Holopainen S Pauliina Turunen Harri Sihto Isabel Burghardt Heikki Joensuu Olli Tynninen Juha Jääskeläinen Michael Weller Kaisa Lehti Reijo Käkelä Pirjo Laakkonen |
| author_sort | Vadim Le Joncour |
| collection | DOAJ |
| description | Abstract The current clinical care of glioblastomas leaves behind invasive, radio‐ and chemo‐resistant cells. We recently identified mammary‐derived growth inhibitor (MDGI/FABP3) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient‐derived glioma cells via lysosomal membrane permeabilization (LMP). In a preclinical model, treatment of glioma‐bearing mice with an antihistaminergic LMP‐inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re‐positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo‐resistant glioma cells from sustaining disease progression and recurrence. |
| first_indexed | 2024-03-07T17:05:09Z |
| format | Article |
| id | doaj.art-c1eac63859984fbf8aeb614cf57f36f3 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:05:09Z |
| publishDate | 2019-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-c1eac63859984fbf8aeb614cf57f36f32024-03-03T02:48:23ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-06-01116n/an/a10.15252/emmm.201809034Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilizationVadim Le Joncour0Pauliina Filppu1Maija Hyvönen2Minna Holopainen3S Pauliina Turunen4Harri Sihto5Isabel Burghardt6Heikki Joensuu7Olli Tynninen8Juha Jääskeläinen9Michael Weller10Kaisa Lehti11Reijo Käkelä12Pirjo Laakkonen13Translational Cancer Medicine Research Program Faculty of Medicine University of Helsinki Helsinki FinlandTranslational Cancer Medicine Research Program Faculty of Medicine University of Helsinki Helsinki FinlandTranslational Cancer Medicine Research Program Faculty of Medicine University of Helsinki Helsinki FinlandHelsinki University Lipidomics Unit Helsinki Institute of Life Science (HiLIFE) and Molecular and Integrative Biosciences Research Programme University of Helsinki Helsinki FinlandResearch Programs Unit Genome‐Scale Biology University of Helsinki Helsinki FinlandTranslational Cancer Medicine Research Program Faculty of Medicine University of Helsinki Helsinki FinlandDepartment of Neurology and Brain Tumour Center University Hospital Zurich and University of Zurich Zurich SwitzerlandTranslational Cancer Medicine Research Program Faculty of Medicine University of Helsinki Helsinki FinlandDepartment of Pathology Haartman Institute University of Helsinki and HUSLAB Helsinki FinlandKuopio University Hospital Kuopio FinlandDepartment of Neurology and Brain Tumour Center University Hospital Zurich and University of Zurich Zurich SwitzerlandResearch Programs Unit Genome‐Scale Biology University of Helsinki Helsinki FinlandHelsinki University Lipidomics Unit Helsinki Institute of Life Science (HiLIFE) and Molecular and Integrative Biosciences Research Programme University of Helsinki Helsinki FinlandTranslational Cancer Medicine Research Program Faculty of Medicine University of Helsinki Helsinki FinlandAbstract The current clinical care of glioblastomas leaves behind invasive, radio‐ and chemo‐resistant cells. We recently identified mammary‐derived growth inhibitor (MDGI/FABP3) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient‐derived glioma cells via lysosomal membrane permeabilization (LMP). In a preclinical model, treatment of glioma‐bearing mice with an antihistaminergic LMP‐inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re‐positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo‐resistant glioma cells from sustaining disease progression and recurrence.https://doi.org/10.15252/emmm.201809034antihistaminegliomaLMPMDGIPUFA |
| spellingShingle | Vadim Le Joncour Pauliina Filppu Maija Hyvönen Minna Holopainen S Pauliina Turunen Harri Sihto Isabel Burghardt Heikki Joensuu Olli Tynninen Juha Jääskeläinen Michael Weller Kaisa Lehti Reijo Käkelä Pirjo Laakkonen Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization EMBO Molecular Medicine antihistamine glioma LMP MDGI PUFA |
| title | Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization |
| title_full | Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization |
| title_fullStr | Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization |
| title_full_unstemmed | Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization |
| title_short | Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization |
| title_sort | vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization |
| topic | antihistamine glioma LMP MDGI PUFA |
| url | https://doi.org/10.15252/emmm.201809034 |
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