The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells

Abstract

Tumor cells exhibit at least two distinct modes of migration when invading the 3D environment. A single tumor cell's invasive strategy follows either mesenchymal or amoeboid patterns. Certain cell types can use both modes of invasiveness and undergo transitions between them. This work outlines the signaling pathways involved in mesenchymal and amoeboid types of tumor cell motility and summarizes the molecular mechanisms that are involved in transitions between them. The focus is on the signaling of the Rho family of small GTPases that regulate the cytoskeleton-dependent processes taking place during the cell migration. The multiple interactions among the Rho family of proteins, their regulators and effectors are thought to be the key determinants of the particular type of invasiveness. Mesenchymal and amoeboid invasive strategies display different adhesive and proteolytical interactions with the surrounding matrix and the alterations influencing these interactions can also lead to the transitions.

Fig. 1

Different morphologies of the invasive tumor cells. Left mesenchymal morphology of K4 sarcoma cells. Right amoeboid morphology of A3 sarcoma cells (representative modulation contrast image recorded at an invasion depth of 50 μm)

Fig. 2

Interactions among the components of signaling pathways documented to be involved in the MAT/AMT transitions of cells in a 3D environment. The inhibition of the activity of the proteins highlighted in red was shown to trigger amoeboid to mesenchymal transitions. Inactivation of the proteins depicted in green induces a conversion from the mesenchymal to the amoeboid mode of invasiveness. Mesenchymal to amoeboid transitions were also documented in cells expressing activated Cdc42 (Q61L mutation). Rac, a well-established signaling element essential for mesenchymal movement, is also shown, even though the Rac-dependent morphological transitions were not yet thoroughly documented within the 3D environment. Solid lines direct connections, dashed lines indirect connections