In brain metastasis, cancer cells remain in close contact with the existing vasculature and can use vessels as migratory paths—a process known as vessel co-option. However, the mechanisms regulating this form of migration are poorly understood. Here we use ex vivo brain slices and an organotypic in vitro model for vessel co-option to show that cancer cell invasion along brain vasculature is driven by the difference in stiffness between vessels and the brain parenchyma. Imaging analysis indicated that cells move along the basal surface of vessels by adhering to the basement membrane extracellular matrix. We further show that vessel co-option is enhanced by both the stiffness of brain vasculature, which reinforces focal adhesions through a talin-dependent mechanism, and the softness of the surrounding environment that permits cellular movement. Our work reveals a mechanosensing mechanism that guides cell migration in response to the tissue’s intrinsic mechanical heterogeneity, with implications in cancer invasion and metastasis.

在脑转移中，癌细胞与现有脉管系统保持密切接触，并且可以使用血管作为迁移路径——这一过程称为血管共选。然而，人们对调节这种迁移形式的机制知之甚少。在这里，我们使用离体脑切片和器官型体外模型进行血管共选，以表明癌细胞沿脑血管系统的侵袭是由血管和脑实质之间的刚度差异驱动的。影像学分析表明，细胞通过粘附在细胞外基质基底膜上沿血管基底表面移动。我们进一步表明，脑血管系统的刚度（通过踝蛋白依赖机制加强粘着斑）和允许细胞运动的周围环境的柔软性增强了血管共选。我们的工作揭示了一种机械感应机制，该机制指导细胞迁移以响应组织固有的机械异质性，对癌症侵袭和转移产生影响。