Abstract
Abstract Two major obstacles in brain cancer treatment are the blood-tumor barrier (BTB) and quiescent tumor cells. Here we show that Sox2+ tumor cells directly project cellular processes to ensheathe capillaries in medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of β-Catenin. Piezo2 knockout reverses WNT/β-Catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie therapy failures in brain cancer.
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