Dimensional and temporal controls of three-dimensional cell migration by zyxin and binding partners

Abstract

Spontaneous molecular oscillations are ubiquitous in biology. But to our knowledge, periodic cell migratory patterns have not been observed. Here we report the highly regular, periodic migration of cells along rectilinear tracks generated inside three-dimensional matrices, with each excursion encompassing several cell lengths, a phenotype that does not occur on conventional substrates. Short hairpin RNA depletion shows that these one-dimensional oscillations are uniquely controlled by zyxin and binding partners α-actinin and p130Cas, but not vasodilator-stimulated phosphoprotein and cysteine-rich protein 1. Oscillations are recapitulated for cells migrating along one-dimensional micropatterns, but not on two-dimensional compliant substrates. These results indicate that although two-dimensional motility can be well described by speed and persistence, three-dimensional motility requires two additional parameters, the dimensionality of the cell paths in the matrix and the temporal control of cell movements along these paths. These results also suggest that the zyxin/α-actinin/p130Cas module may ensure that motile cells in a three-dimensional matrix explore the largest space possible in minimum time.

Microtubules stabilize cell polarity by localizing rear signals

“…To our knowledge, there has been only one complex model that may be appropriate for addressing cellular oscillations (65,66). However, the main purpose of the study was to explore the range of possible cell behaviors as a result of the interplay between shape, mechanics, and polarity, with oscillation demonstrated as one of the possible behaviors without considering the trigger or underlying control circuit.…”

Three-dimensional cell migration does not follow a random walk

“…where n is the dimension of the extracellular space (which can be 1D, 2D, and 3D) (10,17,26,27), and τ is the time lag between positions of the cell. The autocorrelation function of the cell velocity vector for the PRW model exhibits a single exponential decay…”

“…However, cell migration in vivo often forces cells to remodel, exert pulling forces on, and move through a 3D collagen I-rich matrix. Recent work has demonstrated that mechanisms of 3D migration are often different from their 2D counterparts (9)(10)(11)(12)(13)(14)(15). Migration on 2D dishes, which induces a basal-apical polarization of the cell, is driven by actomyosin contractility of stress fibers between large focal adhesions and the formation of a wide lamellipodium terminated by thin filopodial protrusions at the leading cellular edge (4,16).…”

“…Recent work has also shown how cancer cells in 3D can alternate between a mesenchymal and an amoeboid migratory phenotype depending on the physical properties of the matrix (19,20) and MMP inhibition (17), phenomena that do not occur in the 2D case. Finally, through the zyxin/α-actinin/p130Cas module, 3D cancer cell migration features tight molecular control of the temporal and spatial patterns of movements in the matrix, which do not exist in conventional 2D migration (10).…”

Cas and NEDD9 Contribute to Tumor Progression through Dynamic Regulation of the Cytoskeleton

“…79 Additionally, recent data indicate that zyxin and Cas cooperate to ensure efficient cell migration in three-dimensional cultures. 80 Intravasation of tumor cells into the cardiovascular and lymphatic systems requires invasion through the basement membrane and vessel walls. Invadopodia formation and protease activity play key roles in intravasation, and as discussed in the preceding section, Cas/NEDD9 signaling is important for both of these processes (see Fig.…”