Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancy
Abstract Background Radioresistance presents a major challenge in the treatment of cervical cancer (CC). Apoptotic tumor cells can create an “onco-regenerative niche,” contributing to radioresistance. However, the intercellular signaling mechanisms mediating the transfer of radioresistance from apop...
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BMC
2025-03-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06350-4 |
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| author | Yuan-Run Deng Qiao-Zhi Wu Wan Zhang Hui-Ping Jiang Cai-Qiu Xu Shao-Cheng Chen Jing Fan Sui-Qun Guo Xiao-Jing Chen |
| author_facet | Yuan-Run Deng Qiao-Zhi Wu Wan Zhang Hui-Ping Jiang Cai-Qiu Xu Shao-Cheng Chen Jing Fan Sui-Qun Guo Xiao-Jing Chen |
| author_sort | Yuan-Run Deng |
| collection | DOAJ |
| description | Abstract Background Radioresistance presents a major challenge in the treatment of cervical cancer (CC). Apoptotic tumor cells can create an “onco-regenerative niche,” contributing to radioresistance. However, the intercellular signaling mechanisms mediating the transfer of radioresistance from apoptotic to surviving cancer cells remain unclear. Methods The role of apoptotic tumor cell-derived extracellular vesicles (apoEVs) in mediating radioresistance was investigated through integrated bioinformatics and experimental approaches. The GSE236738 dataset was analyzed to identify potential regulators, with subsequent validation of apoEV-MTA1 function using in vitro and in vivo models. Mechanistic studies focused on caspase-3 activation, p-STAT1 signaling pathway, and dormancy-associated protein networks. Furthermore, therapeutic strategies targeting MTA1 and its downstream signaling were evaluated for radiosensitization potential. Results MTA1 was identified as a critical factor enriched in and transferred by apoEVs from apoptotic tumor cells to neighboring CC cells. Caspase-3 activation facilitated the nuclear export and encapsulation of MTA1 in apoEVs. Transferred MTA1 retained transcriptional activity, activated the p-STAT1 signaling pathway, and induced cellular dormancy via NR2F1, a key dormancy regulator, resulting in increased radioresistance. Knockdown of MTA1 in apoEVs or inhibition of p-STAT1 in recipient cells enhanced radiosensitivity. Furthermore, apoEV-MTA1 promoted tumor radioresistance and reduced survival rates in irradiated cervical cancer mouse model. Conclusions This study demonstrates that apoEV-MTA1 confers radioresistance in CC by promoting cellular dormancy via the p-STAT1/NR2F1 signaling axis. Targeting this pathway could improve radiosensitivity and provide a promising therapeutic strategy for CC patients. Graphic Abstract |
| format | Article |
| id | doaj-art-f56a46c3debc4f5aa96aa89b0f4f34a3 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-f56a46c3debc4f5aa96aa89b0f4f34a32025-08-20T02:56:17ZengBMCJournal of Translational Medicine1479-58762025-03-0123111510.1186/s12967-025-06350-4Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancyYuan-Run Deng0Qiao-Zhi Wu1Wan Zhang2Hui-Ping Jiang3Cai-Qiu Xu4Shao-Cheng Chen5Jing Fan6Sui-Qun Guo7Xiao-Jing Chen8Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical UniversityDepartment of Radiation Oncology, Nanfang Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical UniversityDepartment of Obstetrics and Gynecology, The Third Affiliated Hospital, Southern Medical UniversityDepartment of Gynecology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityAbstract Background Radioresistance presents a major challenge in the treatment of cervical cancer (CC). Apoptotic tumor cells can create an “onco-regenerative niche,” contributing to radioresistance. However, the intercellular signaling mechanisms mediating the transfer of radioresistance from apoptotic to surviving cancer cells remain unclear. Methods The role of apoptotic tumor cell-derived extracellular vesicles (apoEVs) in mediating radioresistance was investigated through integrated bioinformatics and experimental approaches. The GSE236738 dataset was analyzed to identify potential regulators, with subsequent validation of apoEV-MTA1 function using in vitro and in vivo models. Mechanistic studies focused on caspase-3 activation, p-STAT1 signaling pathway, and dormancy-associated protein networks. Furthermore, therapeutic strategies targeting MTA1 and its downstream signaling were evaluated for radiosensitization potential. Results MTA1 was identified as a critical factor enriched in and transferred by apoEVs from apoptotic tumor cells to neighboring CC cells. Caspase-3 activation facilitated the nuclear export and encapsulation of MTA1 in apoEVs. Transferred MTA1 retained transcriptional activity, activated the p-STAT1 signaling pathway, and induced cellular dormancy via NR2F1, a key dormancy regulator, resulting in increased radioresistance. Knockdown of MTA1 in apoEVs or inhibition of p-STAT1 in recipient cells enhanced radiosensitivity. Furthermore, apoEV-MTA1 promoted tumor radioresistance and reduced survival rates in irradiated cervical cancer mouse model. Conclusions This study demonstrates that apoEV-MTA1 confers radioresistance in CC by promoting cellular dormancy via the p-STAT1/NR2F1 signaling axis. Targeting this pathway could improve radiosensitivity and provide a promising therapeutic strategy for CC patients. Graphic Abstracthttps://doi.org/10.1186/s12967-025-06350-4Cervical cancerApoptotic tumor cell-derived extracellular vesicles (apoEVs)MTA1Tumor dormancyRadioresistance |
| spellingShingle | Yuan-Run Deng Qiao-Zhi Wu Wan Zhang Hui-Ping Jiang Cai-Qiu Xu Shao-Cheng Chen Jing Fan Sui-Qun Guo Xiao-Jing Chen Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancy Journal of Translational Medicine Cervical cancer Apoptotic tumor cell-derived extracellular vesicles (apoEVs) MTA1 Tumor dormancy Radioresistance |
| title | Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancy |
| title_full | Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancy |
| title_fullStr | Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancy |
| title_full_unstemmed | Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancy |
| title_short | Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancy |
| title_sort | apoptotic cell derived extracellular vesicles mta1 confer radioresistance in cervical cancer by inducing cellular dormancy |
| topic | Cervical cancer Apoptotic tumor cell-derived extracellular vesicles (apoEVs) MTA1 Tumor dormancy Radioresistance |
| url | https://doi.org/10.1186/s12967-025-06350-4 |
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