title: Collective cancer cell invasion induced by coordinated contractile stresses.
abstract: 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.
authors.affiliation: 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.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Jimenez Valencia
authors.affiliation: 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.
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Wu
authors.affiliation: Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, Maryland, 21218, USA.
authors.forename: Osman N
authors.initials: ON
authors.lastname: Yogurtcu
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, 21218, USA.
authors.forename: Pranay
authors.initials: P
authors.lastname: Rao
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, 21218, USA.
authors.forename: Josh
authors.initials: J
authors.lastname: DiGiacomo
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, 21218, USA.
authors.forename: Inês
authors.initials: I
authors.lastname: Godet
authors.affiliation: 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.
authors.forename: Lijuan
authors.initials: L
authors.lastname: He
authors.affiliation: 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.
authors.forename: Meng-Horng
authors.initials: MH
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Daniele
authors.initials: D
authors.lastname: Gilkes
authors.affiliation: Physical Sciences-Oncology Center and Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, Maryland, 21218, USA.|Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, Maryland, 21218, USA.
authors.forename: Sean X
authors.initials: SX
authors.lastname: Sun
authors.affiliation: 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.|Department of Oncology and Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, 21218, USA.
authors.forename: Denis
authors.initials: D
authors.lastname: Wirtz
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005354:Fibrosarcoma / Q000473:pathology*; D006801:Humans; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness / Q000473:pathology*; D018874:Spheroids, Cellular
chemical_list: D003094:Collagen
keywords: 3D invasion model; fibrosarcoma; spatio-temporal invasion