Abstract
The dissemination route of brain metastases dictates their spatiotemporal distribution, but whether it alters the ultrastructural state of the blood-tumor barrier remains unresolved. Here, we compared a modified hematogenous dissemination model that minimizes extracranial signal confounds with a direct intracranial inoculation model. The hematogenous model produced multifocal brain lesions, whereas the intracranial model formed unifocal masses. Longitudinal bioluminescence imaging revealed significantly different growth rates between models, yet no statistically significant difference in overall survival was detected under the current cohort sizes and humane endpoints. Critically, exploratory transmission electron microscopy at the tumor-brain interface revealed a conserved pathological phenotype of the blood-tumor barrier in established lesions, irrespective of the seeding route. This pattern was characterized by endothelial cell swelling, a discontinuous basement membrane, and retraction of astrocytic end-feet. These findings suggest that while the seeding route determines the macroscopic pattern of disease, the established brain microenvironment imposes a stereotyped mode of neurovascular unit failure. This work provides a methodologically refined platform for studying brain metastasis and presents direct ultrastructural evidence consistent with a conserved blood-tumor barrier pathology, outlining a testable conceptual framework. These hypothesis-generating ultrastructural observations, derived from representative specimens, warrant quantitative validation.
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All data generated or analyzed during this study are included in this published article and its Supplementary Information files. The source data for tumor burden and body weights are provided in Supplementary Data 1.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (NSFC) under Grant 81872489.
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This work was supported by the National Natural Science Foundation of China (NSFC) under Grant 81872489.
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All authors contributed to the study conception and design. Material preparation, animal model establishment, and data collection were performed by Jian Zhao, Yuehua Zhang, Zhigong Wei, and Kai Li. Data analysis was performed by Jian Zhao, Yuehua Zhang, and Zhigong Wei. The first draft of the manuscript was written by Jian Zhao. Dan Li and Yongsheng Wang supervised the project. All authors commented on previous versions of the manuscript and contributed to its critical revision. All authors read and approved the final manuscript.
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All animal experiments were performed in strict accordance with a protocol approved by the Animal Research Ethics Committee of West China Hospital, Sichuan University (Approval No. 20230214012). All procedures were conducted in accordance with the ARRIVE guidelines and relevant national and institutional guidelines for the care and use of laboratory animals.
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Zhao, J., Zhang, Y., Wei, Z. et al. Route-dependent dissemination with conserved blood–tumor barrier ultrastructure in intracranial metastasis models. Sci Rep (2026). https://doi.org/10.1038/s41598-026-37760-z
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DOI: https://doi.org/10.1038/s41598-026-37760-z
