Abstract 5512: Cerebral endothelial FAK paradoxically inhibits brain metastasis in vivo

Abstract

Abstract Introduction: In cancer metastasis in the trunk, the secreted proteins from tumors, such as VEGFs and TNF-α, activate focal adhesion kinase (FAK) in vascular endothelial cells (VECs). The activated FAK promotes VE-cadherin phosphorylation and the expression of cell adhesion molecules, and it facilitates the extravasation of cancer cells. In the cerebral blood vessels, the VECs maintain very strong cell adhesion supported by the surrounding pericytes and astrocytes. The strong barrier of cerebral VECs is called the blood-brain barrier (BBB) and is regulated differently from trunk VECs. Although the role of FAK in trunk metastasis is shown in many studies, its importance in brain metastasis is not verified. In this study, we focused on the role of the cerebral endothelial FAK and compared the role of FAK in brain metastasis with that in trunk metastasis. Methods: We generated tamoxifen-inducible VEC-specific FAK knockout (FAK-cKO) mice (VEcad-CreERT2; Ptk2-flox/flox) and brain metastatic (BrM) cell lines of Ex3LL (murine lung cancer cell line). We intracardially injected BrM cells of Ex3LL into the FAK-cKO mice and analyzed the tumor development using in vivo bioluminescence imaging and a CUBIC tissue clearing system. We also analyzed the intracranially injected mice of the parental and BrM cell lines to evaluate the tumor angiogenesis, which is reported to be promoted by the endothelial FAK. Results: Although FAK-cKO in VECs has been reported to inhibit lung metastasis, brain metastasis was accelerated in FAK-cKO mice compared with control mice. The number of brain metastatic sites increased in FAK-cKO mice, but there was no difference in the individual tumor size. It suggests that the brain metastasis was promoted by FAK-cKO, but that the proliferation of brain metastasis was not promoted by FAK-cKO. Blood vessel density was decreased with irregular shape in the brain tumors of FAK-cKO mice, suggesting that the angiogenesis was inhibited by FAK-cKO. It indicates that the angiogenic function of endothelial FAK in the brain vasculature was not different from that in the trunk. Conclusion: FAK-cKO in VECs exacerbated the brain metastasis of the BrM cells although it has been reported to inhibit the metastasis in the trunk. FAK-cKO in VECs decreased tumor angiogenesis both in the brain and the trunk. It suggests that the regulatory mechanism of cell adhesion and the FAK function in the brain vasculature is partly different from that in the other organs in the body trunk. We need further investigation to elucidate the function of endothelial FAK in brain metastasis. Citation Format: Shoko Noda-Narita, Atsu Aiba. Cerebral endothelial FAK paradoxically inhibits brain metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5512.