Macrophage TBK1 signaling drives the development and outgrowth of breast cancer brain metastasis
Menée à l'aide de modèles murins ainsi que d'échantillons plasmatiques et d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein et présentant des métastases cérébrales, cette étude met en évidence un mécanisme par lequel l'activation de la kinase TBK1 des macrophages associés à la tumeur contribue au développement et à la croissance de métastases cérébrales
Breast cancer brain metastasis (BCBM) is a highly aggressive and lethal form of brain cancer characterized by significant infiltration of Tumor-associated macrophages (TAMs). BCBM cell-derived matrix metalloproteinase 1 (MMP1) activates TANK-binding kinase (TBK1) in TAMs, which, in turn, drives BCBM development and brain metastatic outgrowth via producing granulocyte-macrophage colony-stimulating factor (GM-CSF). Genetic and pharmacologic inhibition of the TBK1–GM-CSF signaling axis suppresses brain metastasis. Therefore, TBK1 represents a viable and actionable therapeutic target for treating BCBM. 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 αVβ5 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.
Proceedings of the National Academy of Sciences , article en libre accès, 2025