Macrophage TBK1 signaling drives the development and outgrowth of breast cancer brain metastasis
成果类型：
Article
署名作者：
Khan, Fatima; Liu, Yang; Whitfield, Donovan; Pang, Lizhi; Ali, Heba; Huang, Yuyun; Zhou, Fei; Hagan, Robert S.; Frenis, Katie; Rowe, R. Grant; Chen, Peiwen
署名单位：
Cleveland Clinic Foundation; Northwestern University; Feinberg School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University System of Ohio; Case Western Reserve University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-12177
DOI：
10.1073/pnas.2420793122
发表日期：
2025-08-26
关键词：
tumor microenvironment
cells
promote
inhibitor
invasion
GROWTH
progression
ikbke
摘要：
Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment that promote breast cancer brain metastasis (BCBM). Here, we identify TANK-binding kinase (TBK1) as a critical signaling molecule enriched and activated in TAMs of BCBM tumors, playing an indispensable role in BCBM development and metastatic outgrowth in the brain. Mechanistically, BCBM cell-secreted matrix metalloproteinase 1 binds to protease-activated receptor 1 and integrin alpha V beta 5 on macrophages, leading to TBK1 activation mediated by the nuclear factor-kappa B pathway. Reciprocally, TBK1-regulated TAMs produce granulocyte-macrophage colony-stimulating factor (GM-CSF) to drive breast cancer cell epithelial-mesenchymal transition, migration, and invasion, ultimately contributing to BCBM development and brain metastatic outgrowth. Inhibition of TBK1 signaling in TAMs or GM-CSF receptor in cancer cells impedes BCBM development and brain metastatic outgrowth. Correspondingly, the TBK1-GM-CSF signaling axis correlates with lower overall survival in patients with BCBM. Thus, TBK1-mediated tumor-TAM symbiotic interaction provides a promising therapeutic target for patients with BCBM.