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.