Dynamic tensile forces drive collective cell migration through three-dimensional extracellular matrices

Abstract

Collective cell migration drives tissue remodeling during development, wound repair, and metastatic invasion. The physical mechanisms by which cells move cohesively through dense three-dimensional (3D) extracellular matrix (ECM) remain incompletely understood. Here, we show directly that migration of multicellular cohorts through collagenous matrices occurs via a dynamic pulling mechanism, the nature of which had only been inferred previously in 3D. Tensile forces increase at the invasive front of cohorts, serving a physical, propelling role as well as a regulatory one by conditioning the cells and matrix for further extension. These forces elicit mechanosensitive signaling within the leading edge and align the ECM, creating microtracks conducive to further migration. Moreover, cell movements are highly correlated and in phase with ECM deformations. Migrating cohorts use spatially localized, long-range forces and consequent matrix alignment to navigate through the ECM. These results suggest biophysical forces are critical for 3D collective migration.

Gradual conversion of cellular stress patterns into pre-stressed matrix architecture during in vitro tissue growth

“…Cells are tightly aligned with respect to their extracellular matrix (ECM) both in vivo and in vitro, suggesting that they actively control ECM organization and fibre alignment [11][12][13][14][15]. Mechanical forces that are generated by the contractile cytoskeletal actomyosin fibres and transmitted to the ECM through focal adhesion complexes, play an important role in this process [16 -23] as well as in morphogenesis at larger length scales [24][25][26].…”

“…On the one hand, it is known that cellular forces are required for fibre assembly [27,28], and that these forces influence the organization, mechanical state and conformation of the ECM [21,[29][30][31][32]. On the other hand, the spatial arrangement and mechanical state of the ECM influences the ability of cells to spread, migrate, proliferate and generate forces [33 -36], resulting in continuous feedback between cells and the surrounding ECM [11,21,23,37]. Although it has been shown that forces can also be powerful signals for cells to communicate and synchronize over large distances [22,38,39], such long-range interactions are as yet poorly understood, being so far studied mostly in reconstituted or decellularized ECM on relatively short timescales [39 -42].…”

Pushing, pulling, and squeezing our way to understanding mechanotransduction

“…Epithelial cells, which were seeded into the wells, then coalesced to form intact tissues. Fluorescent microspheres embedded within the surrounding collagen gel were used to estimate the mechanical forces exerted by both quiescent [89] and collectively migrating epithelial tissues [91] during 3D culture. This technique has been used to correlate levels of mechanical stress with changes in epithelial gene expression [92] and signal transduction [93].…”

Making Heads or Tails of It: Cell–Cell Adhesion in Cellular and Supracellular Polarity in Collective Migration

“…In leader cells, MRTF-B translocates to the nucleus on activation of RhoA, which is induced by the loss of E-cadherin-based junctions. In the nucleus, MRTF-B interacts with Trim27 and up-regulates b1-integrin expression by inhibiting the b1-integrin-specific miRNA-124 (Kato et al 2014;Gjorevski et al 2015). Previous work has implicated MRTFs as cofactor of serum response factor (SRF) in transcriptional regulation of many actin regulators involved in cell migration downstream from Rho GTPases (Olson and Nordheim 2010).…”