Multiple mechanisms of 3D migration: the origins of plasticity

Abstract

Cells migrate through 3D environments using a surprisingly wide variety of molecular mechanisms. These distinct modes of migration often rely on the same intracellular components, which are used in different ways to achieve cell motility. Recent work reveals that how a cell moves can be dictated by the relative amounts of cell-matrix adhesion and actomyosin contractility. A current concept is that the level of difficulty in squeezing the nucleus through a confining 3D environment determines the amounts of adhesion and contractility required for cell motility. Ultimately, determining how the nucleus controls the mode of cell migration will be essential for understanding both physiological and pathological processes dependent on cell migration in the body.

Figure 1

Regulators of the plasticity of cell migration in 3D environments. The choice of each distinct mode of cell migration may require a combination of two variables, the strength of cell-matrix adhesion and the degree of actomyosin contractility. Primary human fibroblasts are currently the only cell type known to span the range of established cell migration phenotypes. (a) Lobopodial fibroblasts require cell-matrix adhesion and actomyosin contractility to move efficiently through cross-linked extracellular matrix. These cells use actomyosin contractility and robust integrin-mediated adhesion to pull the nucleus forward, like a piston, to pressurize the anterior cell and protrude the plasma membrane. (b) When contractility is reduced in fibroblasts, either by placing then in non-crosslinked matrix or inhibiting RhoA signaling, they switch to lamellipodia-based migration. When adhesion is prevented in confined 3D channels, fibroblasts shift to adhesion- and contractility-independent movement. In addition to fibroblasts, other cell types display similar patterns of motility. (c) Rounded, amoeboid tumor cells are highly contractile, but they rely less on cell-matrix adhesions compared to primary human fibroblasts. Amoeboid tumor cells migrate using small, unstable blebs, yet have enough cell-matrix adhesion to migrate across 2D surfaces. When RhoA is inhibited in amoeboid cells, they switch to a mesenchymal mode of motility, driven by lamellipodial protrusions. (d) When adhesion and adhesion trafficking are re-programed in certain breast cancer cells, they switch from Arp2/3 mediated lamellipodia to formin-mediated, RhoA-dependent actin spikes. (e–h) Finally, many cells that are poorly adhesive and non-motile on 2D substrates can begin to move when confined between two surfaces; these cells are largely contractility-independent and adhesion-independent, migrate using large stable blebs, and exert very little force against the substrate. Future work should establish whether these modes of migration are universal or cell-type specific, as well as establishing if other mechanisms can generate distinct modes of 3D cell migration.