Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier
Objective: Migrasomes, an emerging class of migration-facilitating membranous extracellular vesicles, remain largely uncharted in the intricate landscape of tumor metastasis. This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain meta...
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| Format: | Article |
| Language: | English |
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China Anti-Cancer Association
2025-06-01
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| Series: | Cancer Biology & Medicine |
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| Online Access: | https://www.cancerbiomed.org/content/22/6/690 |
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| author | Song Wang Guohao Gu Xinmiao Xian Jun Li Di Zhang Jianran Guo Anqi Zhang Shen Chen Dong Yan Bingwu Yang Meng An Wei Zhang Bo Fu |
| author_facet | Song Wang Guohao Gu Xinmiao Xian Jun Li Di Zhang Jianran Guo Anqi Zhang Shen Chen Dong Yan Bingwu Yang Meng An Wei Zhang Bo Fu |
| author_sort | Song Wang |
| collection | DOAJ |
| description | Objective: Migrasomes, an emerging class of migration-facilitating membranous extracellular vesicles, remain largely uncharted in the intricate landscape of tumor metastasis. This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis (BCBM). Methods: Migrasomes were isolated and purified from BCBM cells (231-BR) and non-specific organotropic parental counterparts (MDA-MB-231), specifically designated as Mig-BCBM and Mig-BC, respectively. The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model. The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR, western blotting, immunofluorescence, ex vivo fluorescence imaging, and a series of rescue experiments. Results: Mig-BCBM potently augmented the permeability of vascular endothelial layers, which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro. The administration of Mig-BCBM significantly disrupted the blood-brain barrier (BBB) and accelerated BCBM progression in vivo, as evidenced in mouse models, compared to the Mig-BC and control groups. Mechanistically, Mig-BCBM harbored ATF6, a critical transducer of endoplasmic reticulum (ER) stress. Upon internalization into hCMEC/D3 cells, ATF6 elicited robust ER stress responses, culminating in downregulation of ZO-1 and VE-cadherin. Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals. Conclusions: This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis, suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo. |
| format | Article |
| id | doaj-art-ccaeebe1f3014a3aa3a0cabca44ce08c |
| institution | Kabale University |
| issn | 2095-3941 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | China Anti-Cancer Association |
| record_format | Article |
| series | Cancer Biology & Medicine |
| spelling | doaj-art-ccaeebe1f3014a3aa3a0cabca44ce08c2025-08-20T03:28:06ZengChina Anti-Cancer AssociationCancer Biology & Medicine2095-39412025-06-0122669071310.20892/j.issn.2095-3941.2025.0014Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrierSong Wang0Guohao Gu1Xinmiao Xian2Jun Li3Di Zhang4Jianran Guo5Anqi Zhang6Shen Chen7Dong Yan8Bingwu Yang9Meng An10Wei Zhang11Bo Fu12Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Central Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Breast and Thyroid Surgery, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Clinical Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Breast and Thyroid Surgery, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaDepartment of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, ChinaObjective: Migrasomes, an emerging class of migration-facilitating membranous extracellular vesicles, remain largely uncharted in the intricate landscape of tumor metastasis. This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis (BCBM). Methods: Migrasomes were isolated and purified from BCBM cells (231-BR) and non-specific organotropic parental counterparts (MDA-MB-231), specifically designated as Mig-BCBM and Mig-BC, respectively. The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model. The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR, western blotting, immunofluorescence, ex vivo fluorescence imaging, and a series of rescue experiments. Results: Mig-BCBM potently augmented the permeability of vascular endothelial layers, which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro. The administration of Mig-BCBM significantly disrupted the blood-brain barrier (BBB) and accelerated BCBM progression in vivo, as evidenced in mouse models, compared to the Mig-BC and control groups. Mechanistically, Mig-BCBM harbored ATF6, a critical transducer of endoplasmic reticulum (ER) stress. Upon internalization into hCMEC/D3 cells, ATF6 elicited robust ER stress responses, culminating in downregulation of ZO-1 and VE-cadherin. Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals. Conclusions: This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis, suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.https://www.cancerbiomed.org/content/22/6/690breast cancer brain metastasismigrasomeblood-brain barrieratf6endoplasmic reticulum stress |
| spellingShingle | Song Wang Guohao Gu Xinmiao Xian Jun Li Di Zhang Jianran Guo Anqi Zhang Shen Chen Dong Yan Bingwu Yang Meng An Wei Zhang Bo Fu Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier Cancer Biology & Medicine breast cancer brain metastasis migrasome blood-brain barrier atf6 endoplasmic reticulum stress |
| title | Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier |
| title_full | Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier |
| title_fullStr | Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier |
| title_full_unstemmed | Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier |
| title_short | Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier |
| title_sort | cancer cell derived migrasomes harboring atf6 promote breast cancer brain metastasis via endoplasmic reticulum stress mediated disruption of the blood brain barrier |
| topic | breast cancer brain metastasis migrasome blood-brain barrier atf6 endoplasmic reticulum stress |
| url | https://www.cancerbiomed.org/content/22/6/690 |
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