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Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization

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 integ...

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Autores principales: Le Joncour, Vadim, Filppu, Pauliina, Hyvönen, Maija, Holopainen, Minna, Turunen, S Pauliina, Sihto, Harri, Burghardt, Isabel, Joensuu, Heikki, Tynninen, Olli, Jääskeläinen, Juha, Weller, Michael, Lehti, Kaisa, Käkelä, Reijo, Laakkonen, Pirjo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554674/
https://www.ncbi.nlm.nih.gov/pubmed/31068339
http://dx.doi.org/10.15252/emmm.201809034
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author Le Joncour, Vadim
Filppu, Pauliina
Hyvönen, Maija
Holopainen, Minna
Turunen, S Pauliina
Sihto, Harri
Burghardt, Isabel
Joensuu, Heikki
Tynninen, Olli
Jääskeläinen, Juha
Weller, Michael
Lehti, Kaisa
Käkelä, Reijo
Laakkonen, Pirjo
author_facet Le Joncour, Vadim
Filppu, Pauliina
Hyvönen, Maija
Holopainen, Minna
Turunen, S Pauliina
Sihto, Harri
Burghardt, Isabel
Joensuu, Heikki
Tynninen, Olli
Jääskeläinen, Juha
Weller, Michael
Lehti, Kaisa
Käkelä, Reijo
Laakkonen, Pirjo
author_sort Le Joncour, Vadim
collection PubMed
description 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.
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spelling pubmed-65546742019-06-10 Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization Le Joncour, Vadim Filppu, Pauliina Hyvönen, Maija Holopainen, Minna Turunen, S Pauliina Sihto, Harri Burghardt, Isabel Joensuu, Heikki Tynninen, Olli Jääskeläinen, Juha Weller, Michael Lehti, Kaisa Käkelä, Reijo Laakkonen, Pirjo EMBO Mol Med Research Articles 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. John Wiley and Sons Inc. 2019-05-08 2019-06 /pmc/articles/PMC6554674/ /pubmed/31068339 http://dx.doi.org/10.15252/emmm.201809034 Text en © 2019 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Le Joncour, Vadim
Filppu, Pauliina
Hyvönen, Maija
Holopainen, Minna
Turunen, S Pauliina
Sihto, Harri
Burghardt, Isabel
Joensuu, Heikki
Tynninen, Olli
Jääskeläinen, Juha
Weller, Michael
Lehti, Kaisa
Käkelä, Reijo
Laakkonen, Pirjo
Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization
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 Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554674/
https://www.ncbi.nlm.nih.gov/pubmed/31068339
http://dx.doi.org/10.15252/emmm.201809034
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