Amoeboid Transition Occurs in Mammilian Tumor Cells in Response to Changes in Spacial Confinement and Adhesion

Abstract

In this dissertation, we review how plasticity in the modes of cell migration can occur in response to changes in the extracellular matrix. Different modes of migration exhibit varying characteristics, such as cell adhesion, membrane protrusion, and proteolysis, allowing tumor cells to adapt to their current extracellular environment, thus enhancing invasive behavior in response to different antitumorigenic therapies. The combination of various cell migration characteristics results in a distinct mode of single-cell migration, which, for single-cell migration, falls under two general modes, mesenchymal-traction-force motility or amoeboid-propulsion-squeeze motility. Mesenchymal-to-amoeboid transition is known to occur when tumor cells are in a softer matrix with low adhesion and in a high-confinement environment. Under these conditions the tumor cells exhibit higher levels of cortical myosin activity. Amoeboid migration is characterized by high cortical contractility, mediated by increased myosin activity along the cell cortex. Understanding how contractility is increased under changes in adhesion and confinement is important to uncover the possible mechanisms a tumor cell uses to optimize motility. Here, I will introduce a model that explores how the differential regulation of RhoGTPases (Rac1 and RhoA) is modulated with changes in cell-matrix adhesion and cell-matrix confinement to induce mesenchymal-to-amoeboid-transition. In the model, tumor cells in soft matrix are exposed to fewer ligands to which they can bind their integrins and activate Rac1. Loss of Rac1 activation in soft matrix inhibits lamellipodia formation, and the double-negative relationship between Rac1 and RhoA will shift towards RhoA to promote increase cortical myosin activity for amoeboid migration (Figure 1). Myosin activity is further enhanced under confinement through retrograde flow and recycling of transmembrane protein like integrin and syndecan, which results in increase of RhoA-mediated contractility for amoeboid migration.