scholarly journals Zika virus has oncolytic activity against glioblastoma stem cells

2017 ◽  
Vol 214 (10) ◽  
pp. 2843-2857 ◽  
Author(s):  
Zhe Zhu ◽  
Matthew J. Gorman ◽  
Lisa D. McKenzie ◽  
Jiani N. Chai ◽  
Christopher G. Hubert ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Brain Cancer ◽  
Zika Virus ◽  
Oncolytic Virus ◽  
Neural Precursor Cells ◽  
Neural Precursor ◽  
Neural Cells ◽  
Glioblastoma Stem Cells ◽  
Oncolytic Activity

Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.

scholarly journals STEM-12. ZIKA VIRUS TARGETS GLIOBLASTOMA STEM CELLS THROUGH A SOX2-INTEGRIN α vβ 5 AXIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii198-ii199
Author(s):  
Clark Chen ◽  
Sanjay Dhawan ◽  
Zhe Zhu ◽  
Pinar Mesci ◽  
Jeremy Rich
Keyword(s):  
Stem Cells ◽  
Zika Virus ◽  
Oncolytic Virus ◽  
Great Promise ◽  
Normal Brain ◽  
Zikv Infection ◽  
Glioblastoma Stem Cells ◽  
Interferon Stimulated Genes ◽  
Sox2 Expression

Abstract INTRODUCTION Oncolytic virus hold great promise as a platform for glioblastoma therapeutic development. Zika virus (ZIKV) is an oncolytic virus with exquisite selectivity for infecting and killing glioblastoma stem cells (GSCs). Here, we delineate the molecular determinant of this selectivity. METHODS cell-based glioblastoma models, glioblastoma organoid assays, in vivo murine glioblastoma models, ZIKV infectivity assays, gene silencing, ChIP-seq studies. RESULTS In independent models, ZIKV preferentially infected and lysed SOX2+ GSCs. Silencing of SOX2 expression attenuated this preferential infectivity. Of note, ZIKV infection of GSCs was independent of AXL, its putative receptor in normal brain. ChIP-seq experiments revealed that SOX2 bound within the ITGAV locus (encoding the integrin av subunit), and this binding was associated with accumulation of the active chromatin mark H3K27ac. Silencing of SOX2 suppressed ITGAV expression as well as ZIKV infectivity against GSCs, indicating that integrin is required for ZIKV infection. Of integrin b units, only silencing of integrin b5 prevented the killing of GSCs by ZIKV infection, suggesting ZIKV infection required the avb5 integrin. Supporting this hypothesis, blockade of the avb5 integrin substantially reduced ZIKV infection of GSCs in glioblastoma organoid assays and in clinical glioblastoma specimens. Sox2 expression additionally suppress GSC expression of all members of the interferon-stimulated genes (ISG family), thereby suppressing innate anti-viral response to facilitate ZIKV infection. CONCLUSIONS Collectively, our results reveal that ZIKV infection of GSCs is mediated by integrin α vβ 5 leading to SOX2 expression which negatively regulates antiviral immunity thereby facilitating ZIKV infection.

scholarly journals Zika Virus with Increased CpG Dinucleotide Frequencies Shows Oncolytic Activity in Glioblastoma Stem Cells

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 579 ◽  
Author(s):  
Ivan Trus ◽  
Nathalie Berube ◽  
Peng Jiang ◽  
Janusz Rak ◽  
Volker Gerdts ◽  
...  
Keyword(s):  
Stem Cells ◽  
Zika Virus ◽  
Brain Cells ◽  
In Ovo ◽  
Glioblastoma Stem Cells ◽  
Oncolytic Therapy ◽  
Cpg Dinucleotide ◽  
Virus Interactions ◽  
Oncolytic Activity

We studied whether cytosine phosphate–guanine (CpG) recoding in a viral genome may provide oncolytic candidates with reduced infection kinetics in nonmalignant brain cells, but with high virulence in glioblastoma stem cells (GSCs). As a model, we used well-characterized CpG-recoded Zika virus vaccine candidates that previously showed genetic stability and safety in animal models. In vitro, one of the CpG-recoded Zika virus variants had reduced infection kinetics in nonmalignant brain cells but high infectivity and oncolytic activity in GSCs as represented by reduced cell proliferation. The recoded virus also efficiently replicated in GSC-derived tumors in ovo with a significant reduction of tumor growth. We also showed that some GSCs may be resistant to Zika virus oncolytic activity, emphasizing the need for personalized oncolytic therapy or a strategy to overcome resistance in GSCs. Collectively, we demonstrated the potential of the CpG recoding approach for oncolytic virus development that encourages further research towards a better understanding of host–tumor–CpG-recoded virus interactions.

scholarly journals Correction: Zika virus has oncolytic activity against glioblastoma stem cells

2017 ◽  
Vol 214 (10) ◽  
pp. 3145-3145 ◽  
Author(s):  
Zhe Zhu ◽  
Matthew J. Gorman ◽  
Lisa D. McKenzie ◽  
Jiani N. Chai ◽  
Christopher G. Hubert ◽  
...  
Keyword(s):  
Stem Cells ◽  
Zika Virus ◽  
Glioblastoma Stem Cells ◽  
Oncolytic Activity

scholarly journals Zika Virus has Oncolytic Activity Against Glioblastoma Stem Cells

Neurosurgery ◽  
2018 ◽  
Vol 82 (5) ◽  
pp. E113-E114 ◽  
Author(s):  
Jonathan A Lubin ◽  
Ray R Zhang ◽  
John S Kuo
Keyword(s):  
Stem Cells ◽  
Zika Virus ◽  
Glioblastoma Stem Cells ◽  
Oncolytic Activity

scholarly journals Radial glial cells in the adult dentate gyrus: what are they and where do they come from?

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 277 ◽  
Author(s):  
Daniel A. Berg ◽  
Allison M. Bond ◽  
Guo-li Ming ◽  
Hongjun Song
Keyword(s):  
Stem Cells ◽  
Dentate Gyrus ◽  
Radial Glia ◽  
Neural Precursor Cells ◽  
Neural Precursor ◽  
Subgranular Zone ◽  
Adult Neural Stem Cell ◽  
Radial Glial Cells ◽  
Embryonic Origin ◽  
Radial Glial

Adult neurogenesis occurs in the dentate gyrus in the mammalian hippocampus. These new neurons arise from neural precursor cells named radial glia-like cells, which are situated in the subgranular zone of the dentate gyrus. Here, we review the emerging topic of precursor heterogeneity in the adult subgranular zone. We also discuss how this heterogeneity may be established during development and focus on the embryonic origin of the dentate gyrus and radial glia-like stem cells. Finally, we discuss recently developed single-cell techniques, which we believe will be critical to comprehensively investigate adult neural stem cell origin and heterogeneity.

The effect of BMI-1 inhibition on brain cancer stem cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13543-e13543
Author(s):  
Monal Mehta ◽  
Atif J. Khan ◽  
Hatem E. Sabaawy ◽  
Bruce George Haffty
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cell Lines ◽  
Brain Cancer ◽  
Insertion Site ◽  
Stem Cell Markers ◽  
Primary Cells ◽  
Self Renewal

e13543 Background: Glioblastoma (GBM) is the most frequent and deadly brain cancer. Despite tolerance doses of radiation, control of tumor growth within the brain remains a formidable failure. Since the identification of brain cancer stem cells (BCSCs), efforts are underway to target the pathways regulating these cells. The role of Bmi-1 (B-cell specific MMLV insertion site-1), a polycomb member of chromatin-remodeling complex, in BCSCs self-renewal was elucidated. Here we utilize shRNA targeting or pharmacological inhibition of Bmi-1 in GBM cell lines and primary cells as a radiosensitizer to examine the effects of combination therapy on cell death and BCSCs differentiation. Methods: Cells were pre-treated with a Bmi-1 inhibitor before being irradiated. Serial neurosphere assay, a measure of self-renewal potential, was employed to study the effects of radiation, Bmi-1 inhibition, or the combination on BCSCs. The efficacy of this combination on cell death was assessed with MTT and clonogenic assays. Next, the abilities of the inhibitor and radiation to induce differentiation in GBM cell lines and primary cells were quantified. Further, by utilizing a novel zebrafish orthotropic xenograft model, small molecules targeting Bmi-1 and other BCSC pathways can be identified, and used to predict response to combination therapies. Results: Targeting of Bmi-1 in combination with radiation, specifically as a radiosensitizer, induced significant cell death in GBM cells, and was five-fold more effective than radiation only. Importantly, the neurosphere forming ability of BCSCs was severely compromised when the cells were treated with the combination, indicating a potent effect on the stem cell constituency. These effects may be due to loss of BCSC self-renewal potential, increased differentiation, and/or apoptosis as cells treated with the combination exhibited decreased expression of neural stem cell markers and abnormal phenotypes compared to single treatment. Conclusions: Targeting of Bmi-1 may eliminate the subpopulation of radioresistant BCSCs. Bmi-1 inhibition when combined with radiotherapy might provide an effective therapy for GBM patients specifically through its effect on BCSCs by affecting their survival, proliferation, and stem cell features.

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