Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity.

Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2+ tumor cells project cellular processes to ensheathe capillaries in mouse 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 the 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 treatment failures in brain cancer. [Display omitted] • Tumor cells ensheathe capillaries to construct the BTB • BTB-constructing tumor cells respond to mechanical cues • Piezo2 governs WNT/β-catenin signaling in tumor and endothelial cells in the BTB • Piezo2 knockout disrupts BTB and tumor quiescence to elevate chemosensitivity Blood-tumor barrier (BTB) and tumor cell quiescence are two major obstacles in brain cancer treatment. Chen, Momin, and Wanggou et al. show that mechanosensitive tumor cells construct the BTB. Targeting Piezo2 perturbs the BTB and decreases tumor cell quiescence to enhance chemosensitivity of medulloblastoma, the most common pediatric brain cancer. [ABSTRACT FROM AUTHOR]