Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier

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

doi:10.20892/j.issn.2095-3941.2025.0014

Cancer Biology & Medicine (Jun 2025)

Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier

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

Affiliations

Song Wang: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Guohao Gu: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Xinmiao Xian: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Jun Li: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Di Zhang: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Jianran Guo: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Anqi Zhang: Department of Central Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Shen Chen: Department of Breast and Thyroid Surgery, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Dong Yan: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Bingwu Yang: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Meng An: Department of Clinical Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Wei Zhang: Department of Breast and Thyroid Surgery, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China
Bo Fu: Department of Precision Biomedical Key Laboratory, Liaocheng People’s Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China

DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0014
Journal volume & issue: Vol. 22, no. 6
pp. 690 – 713

Abstract

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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.

Published in Cancer Biology & Medicine

ISSN: 2095-3941 (Print)
Publisher: China Anti-Cancer Association
Country of publisher: China
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.cancerbiomed.org/

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