Nonpolarized signaling reveals two distinct modes of 3D cell migration

Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 04/2012; 197(3):439-55. DOI: 10.1083/jcb.201201124
Source: PubMed


We search in this paper for context-specific modes of three-dimensional (3D) cell migration using imaging for phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and active Rac1 and Cdc42 in primary fibroblasts migrating within different 3D environments. In 3D collagen, PIP3 and active Rac1 and Cdc42 were targeted to the leading edge, consistent with lamellipodia-based migration. In contrast, elongated cells migrating inside dermal explants and the cell-derived matrix (CDM) formed blunt, cylindrical protrusions, termed lobopodia, and Rac1, Cdc42, and PIP3 signaling was nonpolarized. Reducing RhoA, Rho-associated protein kinase (ROCK), or myosin II activity switched the cells to lamellipodia-based 3D migration. These modes of 3D migration were regulated by matrix physical properties. Specifically, experimentally modifying the elasticity of the CDM or collagen gels established that nonlinear elasticity supported lamellipodia-based migration, whereas linear elasticity switched cells to lobopodia-based migration. Thus, the relative polarization of intracellular signaling identifies two distinct modes of 3D cell migration governed intrinsically by RhoA, ROCK, and myosin II and extrinsically by the elastic behavior of the 3D extracellular matrix.

Download full-text


Available from: Nuria Gavara
    • "The protrusion thus produced can be used by the cell to pull itself forward, particularly in confined environments [10]. Lamellipodia (polymerization-based) and blebs (contraction-based) can co-exist, or combine to give hybrid modes such as the lobopodia [11]. The close association of the actin cytoskeleton and the cell membrane means that the membrane could affect the cytoskeleton for purely mechanical reasons, unrelated to the role of the membrane in biochemical signaling cascades. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell membrane shape changes are important for many aspects of normal biological function, such as tissue development, wound healing and cell division and motility. Various disease states are associated with deregulation of how cells move and change shape, including notably tumor initiation and cancer cell metastasis. Cell motility is powered, in large part, by the controlled assembly and disassembly of the actin cytoskeleton. Much of this dynamic happens in close proximity to the plasma membrane due to the fact that actin assembly factors are membrane-bound, and thus actin filaments are generally oriented such that their growth occurs against or near the membrane. For a long time, the membrane was viewed as a relatively passive scaffold for signaling. However, results from the last five years show that this is not the whole picture, and that the dynamics of the actin cytoskeleton are intimately linked to the mechanics of the cell membrane. In this review, we summarize recent findings concerning the role of plasma membrane mechanics in cell cytoskeleton dynamics and architecture, showing that the cell membrane is not just an envelope or a barrier for actin assembly, but is a master regulator controlling cytoskeleton dynamics and cell polarity.
    No preview · Article · Jun 2015 · Journal of Physics Condensed Matter
  • Source
    • "Following destabilization of the cortex and transfer of the cytoplasm to the large bleb, contractility remains concentrated at the back of the cell due to the global flow, generating a stabilizing feedback. This can trigger an increase in pressure in the cell, a phenomenon reminiscent of lobopodial migration (Petrie et al., 2012, 2014). The movement of the global actin retrograde flow can also be transmitted to the substratum. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mesenchymal-amoeboid transition (MAT) was proposed as a mechanism for cancer cells to adapt their migration mode to their environment. While the molecular pathways involved in this transition are well documented, the role of the microenvironment in the MAT is still poorly understood. Here, we investigated how confinement and adhesion affect this transition. We report that, in the absence of focal adhesions and under conditions of confinement, mesenchymal cells can spontaneously switch to a fast amoeboid migration phenotype. We identified two main types of fast migration-one involving a local protrusion and a second involving a myosin-II-dependent mechanical instability of the cell cortex that leads to a global cortical flow. Interestingly, transformed cells are more prone to adopt this fast migration mode. Finally, we propose a generic model that explains migration transitions and predicts a phase diagram of migration phenotypes based on three main control parameters: confinement, adhesion, and contractility. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Cell
  • Source
    • "In addition, it is not clear whether lobopodial migration confers an advantage to maintaining directional persistence in aligned 3D matrices, and whether this mode of migration is present in metastatic cells. Because lobopodial migration contains characteristics reminiscent of both mesenchymal and amoeboid migration strategies, lobopodial migration may represent an intermediary in the mesenchymal to amoeboid transition (Petrie et al., 2012). Another study investigating the mechanisms of directional migration in response to matrix topography made use of cell derived matrices to show that Rac localization and signaling is Fig. 2. Adhesions and Rho organize along collagen fibers. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of Rho family GTPases in controlling the actin cytoskeleton and thereby regulating cell migration has been well studied for cells migrating on 2D surfaces. In vivo, cell migration occurs within three dimensional matrices and along aligned collagen fibers with rather different spatial requirements. Recently, a handful of studies coupled with new approaches have demonstrated that Rho GTPases have unique regulation and roles during cell migration within 3D matrices, along collagen fibers, and in vivo. Here we propose that migration on aligned matrices facilitates spatial organization of Rho family GTPases to restrict and stabilize protrusions in the principle direction of alignment, thereby maintaining persistent migration. The result is coordinated cell movement that ultimately leads to higher rates of metastasis n vivo. • Cell migration requires precisely controlled signaling and cytoskeletal dynamic events at the leading and trailing edges to set up front-to-rear polarity. • Rho GTPases are key regulators of cell migration, providing spatial and temporal control of the actin cytoskeleton, microtubules, and cell adhesions. • Rho GTPase act as molecular switches that cycle between GDP-bound (off) and GTP-bound (on). • Rho family GTPases are comprised of the Rho family, RhoA, B, and C, the Rac family, Rac1, 2, 3, RhoG, and Cdc42. • Effectors of Rho GTPases regulate the actin cytoskeleton by affecting polymerization dynamics, branching and bundling, and contraction via actin-myosin interactions. • For more information, see the Cell Migration Consortium Gateway: Copyright © 2014. Published by Elsevier Ltd.
    Full-text · Article · Dec 2014 · The International Journal of Biochemistry & Cell Biology
Show more