Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma
Abstract Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44576-2 |
| _version_ | 1797363053959839744 |
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| author | Weiwei Dai Ruotong Tian Liubing Yu Shasha Bian Yuling Chen Bowen Yin Yuxuan Luan Siqi Chen Zhuoyang Fan Rucheng Yan Xin Pan Yingyong Hou Rong Li Juxiang Chen Minfeng Shu |
| author_facet | Weiwei Dai Ruotong Tian Liubing Yu Shasha Bian Yuling Chen Bowen Yin Yuxuan Luan Siqi Chen Zhuoyang Fan Rucheng Yan Xin Pan Yingyong Hou Rong Li Juxiang Chen Minfeng Shu |
| author_sort | Weiwei Dai |
| collection | DOAJ |
| description | Abstract Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy. |
| first_indexed | 2024-03-08T16:16:19Z |
| format | Article |
| id | doaj.art-6b5e47a3450741aab2f364d93eacec2a |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:16:19Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-6b5e47a3450741aab2f364d93eacec2a2024-01-07T12:35:01ZengNature PortfolioNature Communications2041-17232024-01-0115111910.1038/s41467-023-44576-2Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant gliomaWeiwei Dai0Ruotong Tian1Liubing Yu2Shasha Bian3Yuling Chen4Bowen Yin5Yuxuan Luan6Siqi Chen7Zhuoyang Fan8Rucheng Yan9Xin Pan10Yingyong Hou11Rong Li12Juxiang Chen13Minfeng Shu14Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversitySchool of Basic Medical Sciences, Fudan UniversityDepartment of Pathology, Zhongshan hospital, Fudan UniversityDepartment of Neurosurgery, Shanghai Changhai Hospital, Naval Medical UniversityDepartment of Neurosurgery, Shanghai Changhai Hospital, Naval Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan UniversityAbstract Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy.https://doi.org/10.1038/s41467-023-44576-2 |
| spellingShingle | Weiwei Dai Ruotong Tian Liubing Yu Shasha Bian Yuling Chen Bowen Yin Yuxuan Luan Siqi Chen Zhuoyang Fan Rucheng Yan Xin Pan Yingyong Hou Rong Li Juxiang Chen Minfeng Shu Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma Nature Communications |
| title | Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma |
| title_full | Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma |
| title_fullStr | Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma |
| title_full_unstemmed | Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma |
| title_short | Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma |
| title_sort | overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting igf2bp3 induced netosis in malignant glioma |
| url | https://doi.org/10.1038/s41467-023-44576-2 |
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