Fluid shear stress activates a targetable mechano-metastatic cascade to promote medulloblastoma metastasis

Abstract

Biofluid flow generates fluid shear stress (FSS), a mechanical force widely present in the tissue microenvironment. How brain tumour growth alters the conduit of biofluid and impacts FSS-regulated cancer progression is unknown. Dissemination of medulloblastoma (MB) cells into the cerebrospinal fluid initiates metastasis within the central nervous system. Here, by simulating cerebrospinal fluid dynamics based on magnetic resonance imaging of patients with MB, we discover that FSS is elevated at the cervicomedullary junction. MB-relevant FSS promotes metastasis along the 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 the 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.