Abstract
Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb-based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab-based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells.
Highlights
Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid migration
We found that vimentin was kept entirely within the cell body as opposed to leader blebs (Fig. 1, A, right panels, and B and Movie S1)
This is significant because the cell body resists the motile force generated by the cortical actomyosin flow in leader blebs; vimentin may play an important role in regulating leader bleb– based migration (LBBM) speed [8]
Summary
Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. By combining simvastatin with our recently described approach for confinement of cells, we describe the precise role of a flexible (unbundled) vimentin network in amoeboid human cancer cells [21]. Our data show that the concentration of vimentin and its bundling are potent regulators of mesenchymal and amoeboid migration, mechanics, and survival of human cancer cells in confinement.
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