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

Cancer Biol Med. 2025 Jun 9:j.issn.2095-3941.2025.0014. doi: 10.20892/j.issn.2095-3941.2025.0014. Online ahead of print.

Authors

Song Wang^#^{1

2}, Guohao Gu^#^{1

2}, Xinmiao Xian^{1

2}, Jun Li^{1

2}, Di Zhang^{1

2}, Jianran Guo^{1

2}, Anqi Zhang³, Shen Chen⁴, Dong Yan^{1

2}, Bingwu Yang^{1

2}, Meng An⁵, Wei Zhang⁴, Bo Fu^{1

2}

Affiliations

¹ Department of Precision Biomedical Key Laboratory, Liaocheng People's Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China.
² Shandong Provincial Key Medical and Health Laboratory of Precision Medicine for Aging Intervention and Active Health, Liaocheng 252000, China.
³ Department of Central Laboratory, Liaocheng People's Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China.
⁴ Department of Breast and Thyroid Surgery, Liaocheng People's Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China.
⁵ Department of Clinical Laboratory, Liaocheng People's Hospital, Liaocheng Hospital Affiliated to Shandong First Medical University, Liaocheng 252000, China.

^# Contributed equally.

PMID: 40488414
DOI: 10.20892/j.issn.2095-3941.2025.0014

Abstract

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.

Keywords: ATF6; Breast cancer brain metastasis; blood-brain barrier; endoplasmic reticulum stress; migrasome.

Abstract

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