内皮 FAK 缺失对脑转移和肺转移的相反调控

Introduction: In lung metastasis, tumor-derived factors, such as VEGFs and TNF-alpha, activate focal adhesion kinase (FAK) in vascular endothelial cells (ECs). Activated FAK promotes VE-cadherin phosphorylation and facilitates the extravasation of cancer cells. In contrast, cerebral blood vessels possess much stronger intercellular adhesion, supported by surrounding pericytes and astrocytes. This highly restrictive barrier, known as the blood-brain barrier (BBB), is regulated differently from the endothelial barrier in trunk ECs, and the role of endothelial FAK in brain metastasis remains unclear. In this study, we investigated the function of the cerebral endothelial FAK and compared its contribution to brain metastasis with lung metastasis. Methods: We generated tamoxifen-inducible, EC-specific FAK knockout (FAK-cKO) mice ( VEcad-Cre ERT2 ; FAK-flox/flox ) and established brain metastatic (BrM) and lung metastatic (LuM) cell lines from Ex3LL murine lung cancer cell line. BrM cells were intracardially injected into FAK-cKO mice, and brain metastases were analyzed using the CUBIC tissue-clearing system. Lung metastases were also evaluated following tail vein injection of LuM cells. Results: While endothelial FAK deletion reduced lung metastasis, it conversely increased brain metastasis. The number of brain metastases increased in FAK-cKO mice, whereas the size of individual lesions remained unchanged. These findings suggest that endothelial FAK deletion promotes the initiation of brain metastasis but does not enhance the proliferation of metastatic tumors in the brain. FAK-cKO mice showed no difference in adhesion molecule expression or BBB permeability compared with control mice. However, primary brain ECs from FAK-cKO mice sporadically exhibited internalization of PECAM-1 and VE-cadherin, suggesting endothelial-to-mesenchymal transition (EndoMT). BrM cells co-cultured with these ECs preferentially localized to the dysregulated ECs. This increased susceptibility of FAK-deficient brain ECs to BrM cells suggests that brain endothelial FAK plays a critical role in maintaining BBB integrity and suppressing brain metastasis. Conclusion: Endothelial FAK deletion exacerbated brain metastasis, while reducing lung metastasis. These findings suggest that endothelial FAK differentially regulates vascular barrier functions in the brain and lung, thereby exerting opposing effects on cancer metastasis. Further investigation is required to elucidate the mechanisms by which endothelial FAK preserves BBB integrity and prevents brain metastasis.