Name: how invadopodia help cancer cells spread
Uploaded: 2023-04-30T10:17:01.000Z
Duration: 1 min 35 s
Channel: JoVE

Invasive cancer cells develop special membrane protrusions called invadopodia for migration.
Invadopodia have two main structural components &#8212; F-actin and actin regulators.
The formation of an invadopodium begins with the activation of cortactin &#8212; a nucleation promoting factor.&#160;
Cortactin then recruits cofilin activated WASP and Arp 2/3 complexes near the membrane.
Next, cofilin dissociates from cortactin and starts severing actin filaments to generate free barbed ends for elongation.
The WASP and Arp2/3 proteins initiate new actin branches, pushing the membrane out, and elongating the invadopodium.
Soon after, fascin starts crosslinking the actin filaments to form parallel actin bundles within the invadopodium core.
As the invadopodium matures, the kinesins use the colocalized microtubule network to deliver vesicles with ECM-degrading proteases to the cell membrane.
The cancer cells release these proteases to break down the ECM and intravasate into a blood vessel.
Here, cortactin phosphorylation destabilizes the branched actin network and disassembles the invadopodia.
Similar to intravasation, the circulating cancer cells also use invadopodia to extravasate into the tissue and form secondary tumors.

cancer cell migration through invadopodia

Cancer Cell Migration through Invadopodia

Invadosome is a broad category of cell surface structures with proteolytic activity that&#160; 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.&#160;
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&#160; 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.&#160;

Invadosome is a broad category of cell surface structures with proteolytic activity that&#160; degrades the extracellular matrix (ECM). Invadosomes are ...

cancer-cell-migration-through-invadopodia

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JoVE Core

Cell Biology

Unit 1

Cell Polarization and Migration

KEY TERMS AND CONCEPTS

how invadopodia help cancer cells spread

Invadopodia are cell surface structures that help cancer cells break down the extracellular matrix, or ECM. The ECM is the material outside cells that gives tissues support. Invadopodia are part of a larger group called invadosomes, which also includes structures found in normal cells such as macrophages, endothelial cells, and neurons.

Macrophage podosomes and tumor cell invadopodia are both invadosomes, but they are not the same. Podosomes are short-lived and last only a few minutes. Invadopodia can last for hours and may extend many microns in length. In tumors, they help cells move into blood vessels and out of them during intravasation and extravasation.

Invadopodia share features with lamellipodia and filopodia, especially a core made of filamentous actin. Their formation begins with signaling events that remodel the cytoskeleton and the cell membrane. The actin cytoskeleton is then reorganized into new filaments and branches with help from actin nucleators such as formins and the ARP2/3 complex.

The ARP2/3 complex works best with nucleation-promoting factors, or NPFs, because it is slow to start new actin branches on its own. Cortactin is an NPF and scaffold protein that recruits ARP2/3 to actin filaments and helps stabilize the new branches. Formins support the elongation of unbranched actin filaments, while fascin bundles filaments together. These steps help the invadopodium polymerize actin and mature.

After the invadopodium stabilizes, kinesins move vesicles along nearby microtubules from the Golgi network. These vesicles carry proteases, which are enzymes that cut proteins. The invadopodium membrane releases matrix metalloproteases, cathepsins, and serine proteases to degrade the surrounding ECM. Finally, the actin core breaks down and the invadopodium retracts. Several proteins are involved in this retraction stage, but how they work together is still unclear.

How Invadopodia Help Cancer Cells Spread

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Invadopodia are cell surface structures that help cancer cells break down the extracellular matrix, or ECM. The ECM is the material outside cells that gives tissues support. Invadopodia are part of a larger group called invadosomes, which also includes structures found in normal cells such as macrophages, endothelial cells, and neurons. Macrophage podosomes and tumor cell invadopodia are both invadosomes, but they are not the same. Podosomes are short-lived and last only a few minutes.

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key terms and concepts

Learn how invadopodia form, recruit actin and vesicles, and release proteases that let cancer cells degrade ECM and move through blood vessels.

How Invadopodia Help Cancer Cells Spread | JoVE K12

cell biology

JoVE Core Cell Biology illustrates complex cellular processes in easy-to-understand yet comprehensive animated video lessons. This collection focuses on the essential components and functions of cells, including organelles and membranes, cellular transport, and cell energetics. It is complemented by scientist-in-action videos that demonstrate the application of cell biology in real-world research experiments.

How Invadopodia Help Cancer Cells Spread

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