3D mesenchymal cell migration is driven by anterior cellular contraction that generates an extracellular matrix prestrain

• Published in: Developmental cell Vol. 56; no. 6; pp. 826 - 841.e4
• Main Authors: Doyle, Andrew D., Sykora, Daniel J., Pacheco, Gustavo G., Kutys, Matthew L., Yamada, Kenneth M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.03.2021
• Subjects: 3D microenvironment; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; cancer; Cell Adhesion; cell migration; Cell Movement; Cells, Cultured; contractility; Extracellular Matrix - physiology; Female; fibroblasts; Fibroblasts - cytology; Fibroblasts - physiology; Humans; integrins; mesenchymal; Mesoderm - cytology; Mesoderm - physiology; myosin II; Nonmuscle Myosin Type IIA - metabolism; Stress, Mechanical; fibroblasts; integrins; 3D microenvironment; mesenchymal; contractility; myosin II; cell migration; cancer
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2021.02.017

We describe a cellular contractile mechanism employed by fibroblasts and mesenchymal cancer cells to migrate in 3D collagen gels. During 3D spreading, fibroblasts strongly deform the matrix. They protrude, polarize, and initiate migration in the direction of highest extracellular matrix (ECM) deformation (prestrain). This prestrain is maintained through anterior cellular contractions behind the leading edge prior to protrusion, coordinating a distinct 3D migration cycle that varies between cell types. Myosin IIA is required for strain polarization, generating anterior contractions, and maintaining prestrain for efficient directional cell migration. Local matrix severing disrupts the matrix prestrain, suppressing directional protrusion. We show that epithelial cancer and endothelial cells rarely demonstrate the sustained prestrain or anterior contractions. We propose that mesenchymal cells sense ECM stiffness in 3D and generate their own matrix prestrain. This requires myosin IIA to generate polarized periodic anterior contractions for maintaining a 3D migration cycle. [Display omitted] •A matrix prestrain propels fibroblasts and cancer cells through 3D environments•Anterior contractions sustain the matrix prestrain through enhanced cell protrusion•Both require high myosin II contractility and substantial integrin ligation•The unbalanced front ECM prestrain is highly cell type dependent Doyle et al. show that, in 3D environments, highly migratory mesenchymal cells use anterior contractions localized between the leading edge and nucleusto generate a large extracellular matrix deformation (prestrain) and enhance protrusion. Myosin II contractility and extensive integrin ligation mediate this migration phenotype.