30.6 : Cancer Cell Migration through Invadopodia

Invadosome is a broad category of cell surface structures with proteolytic activity that degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However, invadopodia can last for hours and are many microns in length.

In tumors, invadopodia are essential for cell intravasation and extravasation through blood vessels. They are similar to lamellipodia and filopodia, with a filamentous actin core shaped by actin nucleators and regulatory factors. The lifecycle of an invadopodium is initiated by complex processes involving various signaling cascades that remodel the cytoskeleton and cell membrane. The actin cytoskeleton is reorganized and assembled into new filaments and branches, which requires the activity of actin nucleators such as formins or the ARP2/3 complex.

The Arp2/3 complex requires nucleation-promoting factors (NPF) for optimal activity as it is slow to spontaneously initiate new actin branches. Cortactin, an NPF and scaffold protein, recruits ARP2/3 to filaments, allowing branching of the actin network. Additionally, cortactin can stabilize the newly generated branches. The formin proteins induce the elongation of unbranched actin filaments, while filament bundling is coordinated by fascin. Together these events promote actin filament polymerization and maturation of the invadopodium.

After the invadopodium stabilizes, kinesins use the neighboring microtubules as tracks to transport vesicles with proteases from the Golgi network. These vesicles release enzymes such as matrix metalloproteases, cathepsins, and serine proteases from the membrane of the invadopodia to degrade the surrounding ECM. Lastly, the actin core is disassembled to retract the invadopodium. Several proteins are implicated in the retraction pathway, but it is unclear how these proteins interact during the final stage of the invadopodium life cycle.