Fluid shear stress activates a targetable mechano-metastatic cascade to promote medulloblastoma metastasis
Biofluidflow 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. Dissemination of medulloblastoma(MB) cells into the cerebrospinal fluid(CSF) initiates metastasis within the central nervous system. By simulating CSF dynamics based on magnetic resonance imaging of MB patients, we discovered that FSS is elevated at  the cervicomedullary junction. MB-relevant FSS promotes metastasis along mouse spinal cord. Mechanistically, FSS induces metastatic cell behaviours, including weakened cell-substrate adhesion, increased 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. Overall design: The study included two cell lines, ONS76 and DAOY, each cultured under control conditions or exposed to artificial fluid shear stress (FSS). For every combination of cell line and experimental condition (control or FSS), three biological replicates were generated.