Department of Bioengineering, University of California, Berkeley, CA 94720-1762, USA.
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10334-9. doi: 10.1073/pnas.1118073109. Epub 2012 Jun 11.
Tumor invasion and metastasis are strongly regulated by biophysical interactions between tumor cells and the extracellular matrix (ECM). While the influence of ECM stiffness on cell migration, adhesion, and contractility has been extensively studied in 2D culture, extension of this concept to 3D cultures that more closely resemble tissue has proven challenging, because perturbations that change matrix stiffness often concurrently change cellular confinement. This coupling is particularly problematic given that matrix-imposed steric barriers can regulate invasion speed independent of mechanics. Here we introduce a matrix platform based on microfabrication of channels of defined wall stiffness and geometry that allows independent variation of ECM stiffness and channel width. For a given ECM stiffness, cells confined to narrow channels surprisingly migrate faster than cells in wide channels or on unconstrained 2D surfaces, which we attribute to increased polarization of cell-ECM traction forces. Confinement also enables cells to migrate increasingly rapidly as ECM stiffness rises, in contrast with the biphasic relationship observed on unconfined ECMs. Inhibition of nonmuscle myosin II dissipates this traction polarization and renders the relationship between migration speed and ECM stiffness comparatively insensitive to matrix confinement. We test these hypotheses in silico by devising a multiscale mathematical model that relates cellular force generation to ECM stiffness and geometry, which we show is capable of recapitulating key experimental trends. These studies represent a paradigm for investigating matrix regulation of invasion and demonstrate that matrix confinement alters the relationship between cell migration speed and ECM stiffness.
肿瘤的侵袭和转移受到肿瘤细胞与细胞外基质（ECM）之间的生物物理相互作用的强烈调节。尽管已经在 2D 培养中广泛研究了 ECM 硬度对细胞迁移、黏附和收缩性的影响，但将这一概念扩展到更接近组织的 3D 培养中却具有挑战性，因为改变基质硬度的扰动往往会同时改变细胞的约束。鉴于基质施加的空间障碍可以独立于力学来调节侵袭速度，这种耦合尤其成问题。在这里，我们引入了一种基于微加工的基质平台，该平台具有定义壁硬度和几何形状的通道，可独立改变 ECM 硬度和通道宽度。对于给定的 ECM 硬度，与在宽通道或无约束的 2D 表面上的细胞相比，限制在狭窄通道中的细胞出人意料地迁移得更快，我们将其归因于细胞-ECM 牵引力的极化增加。与在无约束的 ECM 上观察到的双相关系相反，限制还使细胞能够随着 ECM 硬度的升高而越来越快地迁移。非肌球蛋白 II 的抑制会消耗这种牵引力的极化，使迁移速度与 ECM 硬度之间的关系相对不受基质约束的影响。我们通过设计一个多尺度数学模型来在计算机上检验这些假设，该模型将细胞力的产生与 ECM 硬度和几何形状联系起来，我们证明该模型能够再现关键的实验趋势。这些研究代表了研究基质对侵袭的调节作用的范例，并表明基质约束改变了细胞迁移速度与 ECM 硬度之间的关系。
