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

The study reveals an important pathway through which fascin promotes cancer development and provides insight into potential pathways that can 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 locations within 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 why 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 associate at the Randall Center for Cellular and Molecular Biophysics, King’s. College London, UK. “However, it was not known how the movement or function of fascin is controlled within the nucleus, and this hampers our ability to develop treatments that block its role in promoting cancer growth and spread.”

To further understand fascin, the team created a series of cancer cell lines with and without functional fascin, as well as an array of fascin ‘nanobodies’ labeled with fluorescent markers, to alter its location in cells and explore its interactions with other proteins in the 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 without fascin were unable to build nuclear actin bundles to the same extent. Fascin also interacted with another group of important proteins in the cell’s nucleus, called histones. When fascin is not involved in actin bundling, it binds to histone H3 – an important player involved in the organization of DNA within the nucleus.

Given the interaction of fascin with histones, the team examined whether fascin was 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 necessary for cancer cells to trigger their response to DNA damage caused by chemotherapy or radiotherapy . Fascin-depleted cells also had changes in their 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, which promote invasion. So the team wanted to understand whether moving all fascin to the nucleus would prevent the cytoplasmic function of fascin. As they predicted, in cells with extended nuclear fascia, the number of filopodia was significantly reduced because there was no fascia in the cytoplasm to support the assembly of these structures. Cells also invaded less in 3-dimensional scaffolds that mimic tissue surrounding tumors. Importantly, cells that had forced nuclear fascin had significantly reduced growth rates and viability because they accumulated large stable bundles of actin in the nucleus, which prevented them from progressing through the cell cycle. Together, these results show that, instead of trying to find ways to block fascin, forcing it into the nucleus of cancer cells can prevent their growth and movement.

“Our study provides insight into a new role for fascin in controlling nuclear actin assembly to support tumor cell viability,” concludes senior author Maddy Parsons, Professor of Cell Biology at the Randall Center for Cellular and Molecular Biophysics, King’s College in 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 that it promotes the accumulation of fascin in the nucleus of cancer cells, rather than focuses only on targeting it in the cell’s cytoplasm, may be an alternative approach that would prevent tumor growth and spread.”

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