A flexible network of Vimentin intermediate filaments promotes the migration of amoeboid cancer cells through confined environments

Abstract

The spread of tumor cells to distant sites is promoted by their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this, inhibitors of metastasis must account for each motility mode. To this end, here we determine 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. However, the role of Vimentin in amoeboid migration has not been determined. Since amoeboid, leader bleb-based migration occurs in confined spaces and Vimentin is known to be a major determinant of cell mechanical properties, we hypothesized that a flexible Vimentin network is required for fast amoeboid migration. This was tested using our PDMS slab-based approach for the confinement of cells, RNAi, overexpression, pharmacological treatments, and measurements of cell stiffness. In contrast to Vimentin RNAi, inducing the bundling of Vimentin was found to inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Collectively, our data supports a model whereby the perturbation of cell mechanical properties by Vimentin bundling inhibits the invasive properties of cancer cells.

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

“…However, in mouse embryonic fibroblasts, the absence of vimentin IFs promoted migration through small pores [88]. Moreover, loss of vimentin enhanced amoeboid leader bleb-based migration of confined cancer cells [89]. Together these studies suggest that the contribution of vimentin IFs to perinuclear stiffness is required for the preservation of nuclear integrity and constitutes a critical parameter for controlling confined migration (Figure 3).…”

Intermediate Filaments as Potential Target for Cancer 2 Treatment

“…However, in mouse embryonic fibroblasts, the absence of vimentin IFs promoted migration through small pores [87]. Moreover, loss of vimentin enhanced amoeboid, leader bleb-based migration of confined cancer cells [88]. Together these studies suggest that contribution of vimentin IFs to perinuclear stiffness is required for preservation of nuclear integrity and constitutes a critical parameter for controlling confined migration (Figure 3).…”