2. Academic Validation
  3. Reelin-LRP8 signaling mediates brain dissemination of breast cancer cells via abluminal migration

Reelin-LRP8 signaling mediates brain dissemination of breast cancer cells via abluminal migration

  • EMBO Mol Med. 2025 Jun 12. doi: 10.1038/s44321-025-00260-0.
Haofeng Huang # 1,  Min Zhang # 1,  Enyu Huang # 1,  Yongfang Zhao 2,  Xiaoyu Li 1,  Pu Qiu 3,  Cairui Li 4,  Jiahua Tao 5,  Yuanqi Zhang 3,  Lianxiang Luo 5,  Guozhu Ning 6,  Ceshi Chen 2,  Jingjing Zhang 7 8
Affiliations

Affiliations

  • 1 Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, China.
  • 2 Yunnan Key Laboratory of Breast Cancer Precision Medicine, Academy of Biomedical Engineering, Kunming Medical University, 650000, Kunming, China.
  • 3 Department of Breast Surgery, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, China.
  • 4 Dali Bai Autonomous Prefecture People's Hospital (The Third Affiliated Hospital of Dali University), 671000, Dali, China.
  • 5 The First Clinical College & School of Ocean and Tropical Medicine, Guangdong Medical University, 524021, Zhanjiang, China.
  • 6 Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, China. ningguozhu@gdmu.edu.cn.
  • 7 Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, China. jingjing.zhang@gdmu.edu.cn.
  • 8 School of Medical Technology, Guangdong Medical University, 523808, Dongguan, China. jingjing.zhang@gdmu.edu.cn.
  • # Contributed equally.
PMID: 40506610 DOI: 10.1038/s44321-025-00260-0
Abstract

Brain metastasis (BM) remains a significant challenge in breast Cancer (BC) management. While conventional metastatic routes primarily involve hematogenous dissemination, emerging evidence suggests that BC cells can also migrate along the abluminal surface of blood vessels, bypassing the blood-brain barrier (BBB). To investigate this phenomenon, we established a zebrafish xenograft model utilizing GFP-labeled MDA-MB-231 cells, allowing real-time observation of BC cell migration along the posterior cerebral veins. Our findings revealed that LRP8, an Apolipoprotein E receptor, is upregulated in BC patients with brain metastasis. Functional studies demonstrated that LRP8 knockdown significantly inhibited proliferation, migration, and invasion of triple-negative breast Cancer (TNBC) cells both in vitro and in vivo. Mechanistically, LRP8 promotes the activation of CDC42, enhancing filopodia formation and cell motility, a process influenced by the neuronal extracellular matrix protein, Reelin. Furthermore, we demonstrated the therapeutic potential of MEN 10207, a neurokinin-2 receptor antagonist, in inhibiting TNBC cell migration and suppressing BM formation in both zebrafish and mouse models. These findings provide novel insights into the mechanisms underlying extravascular brain dissemination of BC, highlighting the Reelin-LRP8-CDC42 axis as a potential therapeutic target for this devastating complication.

Keywords

Brain Metastasis; Breast Cancer; LRP8; Reelin; Xenografted Model.

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