Researchers have shown that a protein called fascin is transported into the nucleus of cancer cells, where it plays an important role in cell motility and growth – ScienceDaily

The study reveals an important pathway by which fascin promotes cancer development and provides insight into potential pathways that could block its action.

Fascin is known to control the structures that allow cells to move – specifically the assembly of bundles of a protein called actin, which create the tiny “legs” that cancer cells use to migrate to distant places in the body. Fascin is also known to be at much higher levels in most solid tumors, where it helps cancer cells migrate and invade other tissues. This invasion – or “metastasis” – of tumor cells is the main reason many cancers are so difficult to treat

“We have previously shown that fascin resides in the cell’s control center – the nucleus – at certain times of the cell’s growth cycle,” explains lead author Campbell Lawson, research fellow at the Randall Center for Cellular and Molecular Biophysics, King’s College London. Great Britain. “However, it was not known how the movement or function of fascin is controlled in the nucleus, and this has hampered our ability to develop treatments that block its role in promoting cancer growth and spread.”

To better understand fascin, the team created a series of cancer cell lines with and without functional fascin, as well as a set of fascin “nanobodies” labeled with fluorescent markers to alter its location in cells and study its interactions with other proteins in a nucleus.

They found that fascin is actively transported in and out of the nucleus, and once there it supports the assembly of actin bundles. Indeed, cells lacking fascin are unable to build nuclear actin bundles to the same extent. Fascin also interacts with another group of important proteins in the cell nucleus called histones. When fascin is not involved in binding actin, it is bound to histone H3, an important player involved in organizing DNA in the nucleus.

Given the interaction of fascin with histones, the team looked at whether fascin is also involved in DNA repair processes in cancer cells, which helps them survive. They found that DNA repair was impaired in cells lacking fascin, indicating that the protein may be needed by cancer cells to trigger their response to DNA damage caused by chemotherapy or radiation. Fascin-depleted cells also had changes in chromatin structure — the way DNA is packaged in the cell — compared to cells with normal levels of fascin.

Although nuclear fascin plays an important role in nuclear actin assembly, DNA structure and repair, it is also important in the cell cytoplasm, where it helps cancer cells build tiny appendages called filopodia that promote invasion. So the team wanted to know if moving all of the fascin into the nucleus would interfere with the cytoplasmic function of fascin. As they expected, in cells with enhanced nuclear fascin, the number of filopodia was greatly reduced because there was no fascin in the cytoplasm to support the assembly of these structures. The cells also invade less into three-dimensional scaffolds that mimic the tissue surrounding tumors. Importantly, cells that had forced nuclear fascin had significantly reduced growth rates and viability because they assembled large stable actin bundles in the nucleus, which prevented them from progressing through the cell cycle. Taken together, these results suggest that instead of trying to find ways to block fascin, forcing it into the nucleus of cancer cells can prevent them from growing and moving.

“Our study provides insight into a novel role for fascin in controlling nuclear actin bundling to maintain tumor cell viability,” concluded senior author Maddy Parsons, Professor of Cell Biology at the Randall Center for Cellular and Molecular Biophysics, King’s College London . “Given that fascin is at very high levels in many solid tumors but not in normal tissues, this molecule is an interesting therapeutic target.” We propose to promote the accumulation of fascin in the nucleus of cancer cells instead of only focusing on its targeting within the cell. cytoplasm, may be an alternative approach that would prevent both tumor growth and spread.”

Story source:

Materials provided by eLife. Note: Content may be edited for style and length.

Leave a Comment