Uroz Marina, Stoddard Amy E, Sutherland Bryan P, Courbot Olivia, Oria Roger, Li Linqing, Ravasio Cara R, Ngo Mai T, Yang Jinling, Tefft Juliann B, Eyckmans Jeroen, Han Xue, Elosegui-Artola Alberto, Weaver Valerie M, Chen Christopher S
Department of Biomedical Engineering, Boston University, Boston, MA, USA.
The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
Nat Cell Biol. 2024 Dec;26(12):2144-2153. doi: 10.1038/s41556-024-01532-6. Epub 2024 Oct 24.
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，癌细胞与现有的脉管系统保持密切接触，并可将血管用作迁移路径——这一过程称为血管共生。然而，调节这种迁移形式的机制尚不清楚。在这里，我们使用离体脑片和一种用于血管共生的体外器官型模型，以表明癌细胞沿脑血管的侵袭是由血管与脑实质之间的硬度差异驱动的。成像分析表明，细胞通过粘附于基底膜细胞外基质，沿着血管的基底表面移动。我们进一步表明，脑血管的硬度通过一种依赖于踝蛋白的机制加强粘着斑，以及周围环境的柔软度允许细胞移动，都增强了血管共生。我们的研究揭示了一种机械传感机制，该机制响应组织固有的机械异质性来引导细胞迁移，对癌症侵袭和转移具有重要意义。
