4. Regulation of Lamellipodia and Filopodia in Cancer Cells
The intricate dynamics of lamellipodia and filopodia in cancer cells are tightly regulated by a complex network of signaling pathways and regulatory proteins (Figure 1 ) [38–40]. At the forefront of regulating cytoskeletal dynamics are the Rho family of small GTPases, particularly RhoA, Rac1, and Cdc42. These GTPases act as molecular switches, cycling between an active GTP-bound state and an inactive GDP-bound state. The activation of Rho GTPases orchestrates the intricate processes of lamellipodia and filopodia formation [38,39,41]. Activation of RhoA promotes actomyosin contractility, influencing the rear retraction of the cell during migration. This counteracts the protrusive forces generated by lamellipodia, ensuring coordinated cell movement. Rac1 activation stimulates lamellipodia formation by promoting actin polymerization at the leading edge [9,29,39,42]. WASP and Arp2/3 complex are critical regulators of lamellipodia formation, acting downstream of Rac1 activation. Activated by Rac1, WASP binds to the Arp2/3 complex, promoting the nucleation of new actin filaments. This nucleation initiates the formation of branched actin networks characteristic of lamellipodia. Through the branching of actin filaments, Arp2/3 complex facilitates the creation of a dendritic network that drives the protrusion of the plasma membrane during lamellipodia formation. Overall, the WASP-Arp2/3 pathway exemplifies the intricate molecular machinery that governs the dynamics of lamellipodia, allowing cancer cells to extend and retract their leading edges during migration [43–45]. Next, activation of Cdc42 induces filopodia formation by promoting the bundling of actin filaments. It engages with proteins like Ena/VASP, facilitating the elongation of filopodia [9,39]. Ena/VASP family of proteins enhance actin filament elongation and bundling, promoting the formation of parallel actin bundles characteristic of filopodia. They interact with actin barbed ends, inhibiting capping and facilitating filament growth [14,46]. Ena/VASP proteins contribute to filopodia elongation, stability, and navigation through the tumor microenvironment, ultimately influencing cancer cell invasion and metastasis [47,48]. Overall, the coordinated activity of regulatory proteins, such as WASP and Ena/VASP, ensures the precise orchestration of lamellipodia and filopodia dynamics, allowing cancer cells to respond to external stimuli and navigate through complex tissue environments.