Fibroblasts Lead the Way: A Unified View of 3D Cell Motility

Abstract

Primary human fibroblasts are remarkably adaptable, able to migrate in differing types of physiological 3D tissue and on rigid 2D tissue culture surfaces. The crawling behavior of these and other vertebrate cells has been studied intensively, which has helped generate the concept of the cell motility cycle as a comprehensive model of 2D cell migration. However, this model fails to explain how cells force their large nuclei through the confines of a 3D matrix environment and why primary fibroblasts can use more than one mechanism to move in 3D. Recent work shows that the intracellular localization of myosin II activity is governed by cell-matrix interactions to both force the nucleus through the extracellular matrix and dictate the type of protrusions used to migrate in 3D.

Cancer cell motility: lessons from migration in confined spaces

“…In a 3D microenvironment, cells can migrate using thin fan-like protrusions at the distal ends of F-actin-enriched pseudopodia, adhesions to the matrix and polarization of cortactin, Wiskott–Aldrich syndrome protein (WASP), RAC1, CDC42 and phosphatidyl-inositol-3,4,5-trisphosphate (PIP) 71,73 or using actin-rich, wedge-like protrusions that fill the available pore opening 42 . When the cellular adhesion machinery is intact and cells can remodel the matrix by exerting traction forces on the surrounding matrix, tumour cells migrate using pseudopods, often alongside MMP activity 57 .…”

Nuclear migration events throughout development

“…Fibroblasts can migrate through 3D-matrices in multiple ways (recently reviewed in Petrie and Yamada, 2015), one of which is by using blunt, cylindrical protrusions called lobopodia that are dependent on Rho, but not Rac or Cdc42 (Petrie et al, 2012). Lobopodia migration relies on the existence of a cellular pressure gradient.…”

Mesenchymal Cell Invasion Requires Cooperative Regulation of Persistent Microtubule Growth by SLAIN2 and CLASP1

“…Importantly, cell migration modes in 3D matrices are determined by cell shape characteristics (Friedl and Gilmour, 2009). In particular, mesenchymal cell motility, found in fibroblasts, endothelial cells, embryonic cells undergoing epithelial-mesenchymal transition (EMT) and in invasive tumors requires formation of long pseudopods (Cheung et al, 2013; Clark and Vignjevic, 2015; Friedl and Gilmour, 2009; Grinnell and Petroll, 2010; Petrie and Yamada, 2015). …”

“…In contrast, MTs are viewed as signaling and trafficking platforms that modulate cell shape by indirectly regulating Rho GTPases, substrate adhesion and polarity (Etienne-Manneville, 2013; Gierke and Wittmann, 2012; Petrie and Yamada, 2015; Rhee et al, 2007). Depletion of the plus end tracking protein (+TIP) EB1 caused invasion defects in hepatocyte growth factor-stimulated canine epithelial cells (Gierke and Wittmann, 2012).…”