Collective cancer cell invasion induced by coordinated contractile stresses
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Angela M. Jimenez Valencia1,2, Pei-Hsun Wu1,2, Osman N. Yogurtcu3, Pranay Rao1, Josh DiGiacomo1, Inês Godet1, Lijuan He1,2, Meng-Horng Lee1,2, Daniele Gilkes1,2, Sean X. Sun2,3, Denis Wirtz1,2,4
1Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, 21218, USA
2Physical Sciences-Oncology Center and Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland, 21218, USA
3Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, Maryland, 21218, USA
4Department of Oncology and Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21218, USA
Denis Wirtz, e-mail: [email protected]
Keywords: spatio-temporal invasion, fibrosarcoma, 3D invasion model
Received: June 01, 2015 Accepted: October 20, 2015 Published: October 30, 2015
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.
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