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.

脑癌治疗的主要障碍包括限制大多数治疗药物进入的血肿瘤屏障 (BTB) 和抵抗传统化疗的静止肿瘤细胞。在这里，我们显示 Sox2 ⁺肿瘤细胞将细胞过程投射到小鼠髓母细胞瘤 (MB) 中的毛细血管鞘中，这一过程取决于机械敏感离子通道 Piezo2。MB 开发组织硬度梯度作为到毛细血管的距离的函数。Sox2 ⁺肿瘤细胞感知基质硬度以维持局部细胞内钙、肌动球蛋白张力和粘附以促进细胞过程生长和细胞表面 β- 连环蛋白的螯合。^{Piezo2 敲除逆转 Sox2 +}之间的 WNT/β-连环蛋白信号传导状态肿瘤细胞和内皮细胞，损害 BTB，减少 Sox2 ⁺肿瘤细胞的静止，并显着增强 MB 对化疗的反应。我们的研究表明，机械敏感性肿瘤细胞构建 BTB 以掩盖肿瘤化学敏感性。靶向 Piezo2 解决了导致脑癌治疗失败的 BTB 和肿瘤静止特性。