Jimenez Valencia Angela M, Wu Pei-Hsun, Yogurtcu Osman N, Rao Pranay, DiGiacomo Josh, Godet Inês, He Lijuan, Lee Meng-Horng, Gilkes Daniele, Sun Sean X, Wirtz Denis
Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, 21218, USA.
Physical Sciences-Oncology Center and Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland, 21218, USA.
Oncotarget. 2015 Dec 22;6(41):43438-51. doi: 10.18632/oncotarget.5874.
The physical underpinnings of fibrosarcoma cell dissemination from a tumor in a surrounding collagen-rich matrix are poorly understood. Here we show that a tumor spheroid embedded in a 3D collagen matrix exerts large contractile forces on the matrix before invasion. Cell invasion is accompanied by complex spatially and temporally dependent patterns of cell migration within and at the surface of the spheroids that are fundamentally different from migratory patterns of individual fibrosarcoma cells homogeneously distributed in the same type of matrix. Cells display a continuous transition from a round morphology at the spheroid core, to highly aligned elongated morphology at the spheroid periphery, which depends on both β1-integrin-based cell-matrix adhesion and myosin II/ROCK-based cell contractility. This isotropic-to-anisotropic transition corresponds to a shift in migration, from a slow and unpolarized movement at the core, to a fast, polarized and persistent one at the periphery. Our results also show that the ensuing collective invasion of fibrosarcoma cells is induced by anisotropic contractile stresses exerted on the surrounding matrix.
纤维肉瘤细胞从富含胶原蛋白的周围基质中的肿瘤扩散的物理基础尚不清楚。在这里，我们表明，嵌入三维胶原蛋白基质中的肿瘤球体在侵袭前会对基质施加巨大的收缩力。细胞侵袭伴随着球体内部和表面复杂的时空依赖性细胞迁移模式，这与均匀分布在同一类型基质中的单个纤维肉瘤细胞的迁移模式有根本不同。细胞呈现出从球体核心的圆形形态到球体周边高度排列的细长形态的连续转变，这取决于基于β1整合素的细胞-基质粘附和基于肌球蛋白II/ROCK的细胞收缩性。这种各向同性到各向异性的转变对应于迁移的转变，从核心处缓慢且无极化的运动，到周边处快速、极化且持续的运动。我们的结果还表明，随后纤维肉瘤细胞的集体侵袭是由施加在周围基质上的各向异性收缩应力诱导的。
