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.

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Available from: Nuria Gavara, Oct 07, 2015
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    • "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. "
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    • "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. "
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    • "Furthermore, CMACs detect ECM composition and rigidity and integrate this into the cell's protrusion rate, migratory speed, and motility mode, while concomitantly transmitting contractile forces from the cell's actin cytoskeleton to the ECM (Lock et al. 2008, Huttenlocher and Horwitz 2011). As an example of the former, fibroblasts can alternate between modes of lamellipodia-and lobopodiabased motility, depending on ECM rigidity and composition (Petrie et al. 2012). "
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