Breakthrough discovery about cell migration may finally help us defeat cancer

Cells in the human body have distinct roles – some remain stationary, while others move to perform critical functions. Migratory cells rely delicate, finger-like protrusions called filopodia that extend from the cell membrane and allow the cell to sense and navigate its environment.

In healthy cells, filopodia play a vital role in processes like the immune response, where they help immune cells reach infection sites swiftly.

However, filopodia also contribute to disease, particularly in cancer. Metastatic cancer cells exploit these structures to invade new tissues, facilitating the spread of cancer throughout the body.

Cracking the filopodia code

A long-standing question in cell biology has been how filopodia’s protein bundles form and function. For over forty years, researchers have sought to understand the structural mechanics behind these cellular extensions.

Now, scientists at Rockefeller University’s Laboratory of Structural Biophysics and Mechanobiology have made a recent discovery that may help solve a major piece of this puzzle.

The study, published in Nature Structural & Molecular Biology, sheds light on how the protein scaffolding in filopodia is assembled at the atomic level. These findings could play a crucial role in refining cancer treatments that are designed to halt metastasis.

“Understanding the structure of filopodia and the changes they undergo may help to refine these therapies or inspire new ones,” said Rui Gong, the study’s first author.

Complexity of filopodia in cancer

Filopodia rely on hexagonal bundles of actin filaments, strengthened and reinforced by a crucial protein called fascin.

Actin, a fundamental component of the cytoskeleton, is responsible for maintaining a cell’s shape and enabling movement. However, actin alone is weak and ineffective. A single actin filament cannot support a structure or drive movement.

“It’s like a floppy noodle,” explained Gregory M. Alushin, head of the Rockefeller Lab. “It’s not very strong, and it can’t do anything. Actin filaments have to be gathered into higher-order assemblies such as bundles to carry out any useful job.”

Fascin: Key to filopodia’s strength

Fascin plays a critical role in stabilizing these actin bundles, bridging the filaments together and forming the strong yet flexible structures required for filopodia to function.

These bundles must strike a delicate balance: they need enough strength to protrude from the cell membrane, yet they must also remain flexible enough to move and respond to environmental stimuli.

“They hit a sweet spot between strength and flexibility,” explained Alushin.

Despite the known importance of fascin, the precise mechanics of how it assembles actin bundles into filopodia have remained elusive for decades. The challenge has been in visualizing this process at a molecular level.

Challenge in understanding fascin

For years, scientists struggled to understand how fascin assembles filopodia’s hexagonal bundles. Early experiments in the 1970s attempted to model this process using wooden dowels to represent actin filaments, and small wooden pieces as fascin-like bridges.

However, researchers found it impossible to create stable bundles without distorting the fascin structures.

In recent years, advances in imaging technologies such as cryo-electron microscopy (cryo-EM) and tomography provided the first glimpses of filopodia’s internal architecture.

However, these images were blurry and lacked sufficient resolution to reveal the intricate details of how fascin interacts with actin filaments.

Now, the Rockefeller team has made a significant breakthrough. Using an advanced computational image analysis technique, the researchers achieved the first clear, atomic-level images of fascin proteins bridging actin filaments.

This represents a major leap forward in understanding how the scaffolding of filopodia is constructed.

Filopodia assembly and cancer cells

By refining their computational image analysis method, first developed in 2022, the researchers were able to remove noise from their images and reveal an unprecedented level of structural detail.

“We saw real bundles composed of thousands of fascin molecules and hundreds of actin filaments, and we were able to map their spatial positioning,” Gong explained. “We saw how the structure of fascin gives rise to its function as an actin bundler and figured out the detailed chemistry of its actin binding sites.”

One of the most surprising findings was the discovery of fascin’s high degree of flexibility and adaptability. Unlike other proteins that follow rigid assembly patterns, fascin is remarkably improvisational.

Instead of adhering to a single binding strategy, it can adjust its position and shape depending on the arrangement of the actin filaments.

Fascinating versatility of fascin molecules

Fascin appears to have evolved this versatility as a way to accommodate actin filaments, which are naturally twisted and uneven. Since actin filaments are not ideal building materials for creating firm, uniform structures, fascin overcomes this challenge by acting as a molecular hinge.

“A fascin protein can accommodate all kinds of imperfections. It acts like a molecular hinge that can hold a number of intermediary positions between open and closed. It can also rotate its position for a better fit,” said Alushin.

Despite being a relatively small and simple protein, fascin exhibits highly complex physical behaviors. Its ability to shift and adapt its binding positions allows it to form the strong yet flexible hexagonal bundles necessary for filopodia to function.

Filopodia, fascin, and metastatic cancer

Fascin plays a crucial role in cancer’s ability to spread in the body. In migratory cells, an overabundance of fascin leads to an uncontrolled filopodia-building process, which accelerates metastasis.

In stationary cells, such as epithelial cells, excessive fascin expression can give them an abnormal ability to move – causing them to break away from their normal environment and invade other tissues.

“When this over-expression happens in cells that should be locked into place, such as epithelial cells, they can build filopodia, which they’re not supposed to have,” Alushin explained. “Then they can crawl away from their neighbors and in the process abandon their regular cellular functions.”

Because of its role in cancer progression, fascin has become a key target for cancer therapies. Several fascin inhibitors are currently in clinical trials, with the aim to prevent cancer cells from forming filopodia and migrating.

The Rockefeller team’s findings could improve the design of these inhibitors. Previously, researchers believed that these drugs worked by blocking fascin’s actin binding sites.

However, the new study suggests a different mechanism: these inhibitors prevent fascin from undergoing the shape changes required to fit into its binding location.

Future cancer therapies

This new understanding of fascin’s structural behavior may lead to more effective cancer treatments. By preventing fascin from adapting and forming stable filopodia bundles, scientists may be able to halt metastatic cancer cells in their tracks.

“We’ve been able to detail essential design principles for the bundles, which could be really helpful information for finding new ways to interfere with their construction,” noted Alushin.

Beyond cancer, this research opens the door for further exploration of other cellular processes that rely on actin bundling.

The ability to visualize complex protein networks at an atomic level represents a major technological leap, providing new tools for scientists studying cell movement, immune responses, and even neurological functions.

With this newfound clarity, researchers can now develop more precise strategies for targeting fascin and preventing the metastasis of cancer cells.

By continuing to investigate the forces that drive cellular movement, scientists may unlock new ways to stop cancer from spreading, which would bring hope for more effective treatments in the future.

The study is published in the journal Nature Structural & Molecular Biology.

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