2. Academic Validation
  3. Lipocalin-2 drives brain metastatic progression through reciprocal tumor-microenvironment interactions in lung cancer

Lipocalin-2 drives brain metastatic progression through reciprocal tumor-microenvironment interactions in lung cancer

  • Signal Transduct Target Ther. 2025 Dec 24;10(1):417. doi: 10.1038/s41392-025-02514-2.
Yixiang Zhu # 1 2,  Jian Zhang # 1,  Danming He # 1 3,  Hongqing Cai 4,  Yan He 5,  Li Yuan 1,  Sini Li 5,  Yucheng Dong 6,  Wei Zhuang 1,  Zhijie Wang 1,  Jianchun Duan 1,  Xue Zhang 1,  Zixiao Ma 1,  Hua Bai 7,  Jie Wang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 2 Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • 3 Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, China.
  • 4 Department of Neurosurgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 5 Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 6 Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 7 State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. baihuahb@sina.com.
  • 8 State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. zlhuxi@163.com.
  • # Contributed equally.
PMID: 41436606 DOI: 10.1038/s41392-025-02514-2
Abstract

Brain metastasis is a major contributor to mortality in patients with lung Cancer. The unique microenvironment of the brain plays a critical role in the initiation and progression of brain metastases (BM), yet the molecular mechanisms underlying tumor-microenvironment interactions remain poorly understood. Here, we demonstrate that upregulation of lipocalin-2 (LCN2) in tumor cells promotes brain metastatic progression by orchestrating crosstalk among metastatic tumor cells, astrocytes, and macrophages. Brain metastatic tumor cells secrete LCN2, which binds to SLC22A17 on astrocytes, activating JAK2/STAT3 signaling and inducing astrocyte activation and chemokine secretion, thereby facilitating macrophage recruitment. In turn, macrophages secrete IL-1β, which further upregulates LCN2 expression in tumor cells. Prophylactic administration of the IL-1 receptor antagonist anakinra inhibits BM formation, whereas therapeutic administration alone is ineffective. However, treatment with the STAT3 Inhibitor SH4-54, either alone or in combination with anakinra, significantly suppressed tumor growth in the BM. Furthermore, tumor-secreted LCN2 can bind to SLC22A17 on tumor cells, activating JAK2/STAT3 signaling and promoting VEGF-A expression and release, which enhances tumor neovascularization. Inhibition of this axis with SH4-54, bevacizumab, or their combination effectively reduces the tumor burden in BM-bearing mice. These findings underscore the central role of LCN2 in driving brain metastasis and highlight a potential therapeutic strategy for targeting brain metastatic lung Cancer.

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