3.1. Lamellipodia- and filopodia-driven cancer cell migration and invasion
Lamellipodia are instrumental in mediating cancer cell invasion by orchestrating the degradation of the ECM. Lamellipodia play a role in forming invadopodia – specialized membrane structures that focus proteolytic activity, facilitating localized ECM degradation [9]. This process is facilitated by the secretion of matrix metalloproteinases (MMPs) and other proteolytic enzymes, enabling cancer cells to breach physical barriers and invade surrounding tissues [27]. The dynamic protrusions of lamellipodia create focal points for the assembly of integrins, transmembrane receptors that connect the cell to the ECM, fostering adhesion and promoting localized matrix degradation [28,29]. In aggressive cancers, elevated expression of MMPs in lamellipodia correlates with increased invasive potential. The spatiotemporal regulation of ECM degradation by lamellipodia is critical for tumor progression, allowing cancer cells to navigate through the intricate matrix and invade neighboring tissues [30]. Additionally, lamellipodia extend beyond their role in ECM degradation to facilitate dynamic interactions with neighboring cells. Adhesion structures formed by lamellipodia, such as focal adhesions, not only promote stable attachments to the ECM but also enable communication between cancer cells and surrounding stromal or immune cells [31]. This intercellular crosstalk influences collective migration, allowing groups of cancer cells to coordinate their invasive behavior [9]. Through these interactions, lamellipodia contribute to the creation of a permissive microenvironment that supports invasion and further potentiates metastasis.
Filopodia, with their slender and elongated morphology, serve as sensory extensions that guide cancer cells through the complex terrain of the tumor microenvironment. Rich in receptors and adhesion molecules, filopodia sense and respond to chemotactic gradients, allowing cancer cells to navigate toward specific regions within the tumor. Through dynamic probing and sensing, filopodia facilitate the recognition of guidance cues, such as growth factors and chemokines, directing cancer cells towards blood vessels or areas of increased stromal support. This guidance is critical for the spatial organization of cancer cells within the tumor, influencing invasion patterns and ultimately shaping the metastatic potential of the cancer [25,26]. Filopodia play a crucial role in the metastatic cascade, particularly during extravasation, where cancer cells exit the bloodstream and invade distant tissues [18]. As cancer cells intravasate into the bloodstream, filopodia aid in their interaction with endothelial cells, facilitating the adhesion to and transmigration through the vascular endothelium [32]. Once in the extravascular space, filopodia continue to contribute to metastasis by guiding cancer cells through the foreign microenvironment. The ability of filopodia to establish contacts with neighboring cells, including stromal cells and other cancer cells, enhances their invasive potential. Filopodia-driven invasion is thus a key determinant in the establishment of secondary tumor foci, shaping the metastatic spread of cancer cells [9].