Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization

Joncour, Vadim Le; Filppu, Pauliina; Hyvönen, Mervi T.; Holopainen, Minna; Turunen, S.; Sihto, Harri; Burghardt, Isabel; Joensuu, Heikki; Tynninen, Olli; Jääskeläinen, Juha E.; Weller, Michael; Lehti, Kaisa; Käkelä, Reijo; Laakkonen, Pirjo

doi:10.15252/emmm.201809034

Cited by 44 publications

(57 citation statements)

References 62 publications

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“…Notably, modulation of MDGI/FABP3 strongly altered the GBM cells' ability to co-opt blood vessels as evident in the histological analysis [52]. Pharmacological targeting of the MDGI/FABP3 pathway using the antihistamine Clemastine strongly inhibited perivascular migration and invasive growth [52].…”

Section: Mdgi/fabp3mentioning

confidence: 99%

“…Mammary-derived growth inhibitor (MDGI), also called heart-type fatty acid binding protein (H-FABP/FABP3), enables the intracellular transport of fatty acids [50]. MDGI/ FABP3 was found overexpressed in aggressive mesenchymal GBM and the tumor vasculature, which correlated with poor patient survival [51,52]. Notably, modulation of MDGI/FABP3 strongly altered the GBM cells' ability to co-opt blood vessels as evident in the histological analysis [52].…”

Section: Mdgi/fabp3mentioning

confidence: 99%

“…MDGI/ FABP3 was found overexpressed in aggressive mesenchymal GBM and the tumor vasculature, which correlated with poor patient survival [51,52]. Notably, modulation of MDGI/FABP3 strongly altered the GBM cells' ability to co-opt blood vessels as evident in the histological analysis [52]. Pharmacological targeting of the MDGI/FABP3 pathway using the antihistamine Clemastine strongly inhibited perivascular migration and invasive growth [52].…”

Section: Mdgi/fabp3mentioning

confidence: 99%

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Vessel co-option in glioblastoma: emerging insights and opportunities

2019

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Vessel co-option is the movement of cancer cells towards and along the pre-existing vasculature and is an alternative to angiogenesis to gain access to nutrients. Vessel co-option has been shown as a strategy employed by some glioblastoma (GBM) cells to invade further into the brain, leading to one of the greatest challenges in treating GBM. In GBM, vessel cooption may be an intrinsic feature or an acquired mechanism of resistance to anti-angiogenic treatment. Here, we describe the histological features and the dynamics visualized through intravital microscopy of vessel co-option in GBM, as well as the molecular players discovered until now. We also highlight key unanswered questions, as answering these is critical to improve understanding of GBM progression and for developing more effective approaches for GBM treatment.

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Section: Mdgi/fabp3mentioning

confidence: 99%

Section: Mdgi/fabp3mentioning

confidence: 99%

Section: Mdgi/fabp3mentioning

confidence: 99%

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Vessel co-option in glioblastoma: emerging insights and opportunities

2019

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“…The intracranial glioma model was made by injecting female BALB/cOlaHsd-Foxn1 nu (athymic nude, Institute of Animal Genetics, Edinburgh, UK) mice with patient-derived BT3 glioma cells [29] labeled with luciferase into the frontal right hemisphere of the brain at 9 weeks old. Tumors were monitored for growth via in vivo bioluminescence detection and subjects PET imaged after 12 days.…”

Section: Animal Modelsmentioning

confidence: 99%

“…The orthotopic xenografts of luciferase-expressing patientderived BT3 glioblastoma cells [29] grown in BALB/cOlaHsd-Foxn1 nu mouse brains produced strong in vivo bioluminescence detections and displayed clear differentiation of the tumor mass in in vivo PET and ex vivo autoradiography images (Fig. 3 and Suppl.…”

Section: Orthotopic Glioma Images and Analysesmentioning

confidence: 99%

(2S, 4R)-4-[18F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models

et al. 2020

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Purpose: The glutamine analogue (2S, 4R)-4-[ 18 F]fluoroglutamine ([ 18 F]FGln) was investigated to further characterize its pharmacokinetics and acquire in vivo positron emission tomography (PET) images of separate orthotopic and subcutaneous glioma xenografts in mice. Procedures: [ 18 F]FGln was synthesized at a high radiochemical purity as analyzed by highperformance liquid chromatography. An orthotopic model was created by injecting luciferaseexpressing patient-derived BT3 glioma cells into the right hemisphere of BALB/cOlaHsd-Foxn1 nu mouse brains (tumor growth monitored via in vivo bioluminescence), the subcutaneous model by injecting rat BT4C glioma cells into the flank and neck regions of Foxn1 nu/nu mice. Dynamic PET images were acquired after injecting 10-12 MBq of the tracer into mouse tail veins. Animals were sacrificed 63 min after tracer injection, and ex vivo biodistributions were measured. Tumors and whole brains (with tumors) were cryosectioned, autoradiographed, and stained with hematoxylin-eosin. All images were analyzed with CARIMAS software. Blood sampling of 6 Foxn1 nu/nu and 6 C57BL/6J mice was performed after 9-14 MBq of tracer was injected at time points between 5 and 60 min then assayed for erythrocyte uptake, plasma protein binding, and plasma parent-fraction of radioactivity to correct PET image-derived wholeblood radioactivity and apply the data to multiple pharmacokinetic models. Results: Orthotopic human glioma xenografts displayed PET image tumor-to-healthy brain region ratio of 3.6 and 4.8 while subcutaneously xenografted BT4C gliomas displayed (n = 12) a tumor-to-muscle (flank) ratio of 1.9 ± 0.7 (range 1.3-3.4). Using PET image-derived blood radioactivity corrected by population-based stability analyses, tumor uptake pharmacokinetics fit Logan and Yokoi modeling for reversible uptake. Conclusions: The results reinforce that [ 18 F]FGln has preferential uptake in glioma tissue versus that of corresponding healthy tissue and fits well with reversible uptake models.

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PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells

et al. 2023

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Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3‐kinase–protein kinase B (AKT) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting AKT (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogeneous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined AKT and PDK targeting. Biochemically, the combined AKT and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial apoptosis but failed to induce apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ‐8‐061 (also known as DT‐061), DBK‐1154, and DBK‐1160. We also provide proof‐of‐principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain‐penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A‐elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple‐strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.

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Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization

Cited by 44 publications

References 62 publications

Vessel co-option in glioblastoma: emerging insights and opportunities

Vessel co-option in glioblastoma: emerging insights and opportunities

(2S, 4R)-4-[18F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models

PP2A‐based triple‐strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells

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