Intermediate filaments in cell migration and invasion: the unusual suspects

Cell migration is a multistep process which relies on the coordination of cytoskeletal structures in space and time. While the roles of actin and microtubules have been investigated in great details, the lack of inhibitors and visualizing tools and the large number of proteins forming intermediate filaments (IFs) have delayed the characterization of IF functions during migration. However, a large body of evidence has progressively pointed to changes in IF composition as an important parameter in the regulation of cell migratory properties both during development and tumor invasion. More recent in-depth analyses show that IFs are dynamically reorganized to participate, together with microfilaments and microtubules, to the key steps leading to cell migration.

Introduction

Cell migration is a crucial cellular process during development of multicellular organisms. It also participates in immune responses, tissue renewal and wound healing in the adult. The acquisition of migratory properties plays a key role during pathological situations, and in particular promotes tumor spreading where cancer cells invade adjacent tissues and form metastases. Cell migration relies on a succession of events. The establishment of a front-to-rear polarity axis is followed by membrane protrusion at the leading edge and the formation of new adhesions between the cell and the underlying extracellular matrix. For the cell to move forward, these adhesion sites mature into focal adhesions connected with stress fibers responsible for the contraction of the cell body. The retraction of the cell rear results from the disassembly of focal adhesions and the cell detachment from the substrate [1]. These events are well coordinated in space and time through complex signaling networks which control cytoskeletal rearrangements to promote the structural and functional organization necessary for force generation and migration. Although the contribution of the actin and microtubule cytoskeletal networks is well established [2, 3, 4], the role of intermediate filaments (IFs) is less clear. Nevertheless, IFs form an extensive and elaborate network which connects the cell cortex to intracellular organelles and likely contributes its biophysical properties to the mechanical and motile properties of the cell.

For each cell type, the mode of migration, whether amoeboid or mesenchymal, individual or collective, is determined by specific cell characteristics, which depend on the differentiation stage, and extracellular cues, which can be either chemical or mechanical [5]. IFs are assembled from several protein families (Figure 1a). The expression pattern of IF proteins is tissue specific and developmentally regulated. The expression of specific subsets of IF proteins classically serves as biomarkers to identify the tissue of origin of the tumors. IF expression and composition are also used to determine the progression of cancers, suggesting that they are determining parameters in the cell invasive capacities [6, 7]. However, the specific functions of the ‘IF code’ remain to be unraveled. Here, we review the latest evidence showing that IF composition regulates cell invasion and the current view of how IFs participate to the major events leading to cell migration.