Abstract SY42-01: Targeting fluidic force sensing mechanism to treat brain tumor metastasis

Abstract Biofluid flow generates fluid shear stress (FSS), a mechanical force widely present in tissue microenvironment. How brain tumor growth alters the conduit of biofluid, thereby impacting FSS-regulated cancer progression is unknown. Medulloblastoma (MB), the most common pediatric malignant brain tumor, frequently obstructs the 4th ventricle and infiltrates the cerebrospinal fluid (CSF) conduit. Dissemination of MB cells into the CSF initiates metastasis within the central nervous system. By simulating CSF flow based on magnetic resonance imaging of MB patients, we discovered that FSS is elevated at the cervicomedullary junction. FSS promotes MB metastasis in mice and zebrafish. Mechanistically, FSS promotes cell behaviors conducive to metastatic escape and survival within the nutrient-deprived CSF: FSS weakens cell-substrate adhesion, increases motility, cell clustering, and plasma membrane localization of glucose transporter 1 (GLUT1) to enhance glucose uptake. FSS is perceived by mechanosensitive ion channel PIEZO2, which drives actomyosin contractility-dependent GLUT1 recruitment at the plasma membrane. Genetic targeting of PIEZO2 or pharmacologic inhibition of GLUT1 mitigates metastasis. Collectively, these findings define a targetable FSS-activated mechano-metastatic cascade for the treatment of MB metastasis. Citation Format: Xi Huang. Targeting fluidic force sensing mechanism to treat brain tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY42-01.