Newswise: The study reveals an important pathway by which fascin promotes cancer development and provides insight into possible pathways that could block its action.
Fascin is known to control the structures that allow cells to move, specifically the 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 in the cell’s growth cycle,” says lead author Campbell Lawson, research associate at the Randall Center for Biophysics Cellular and Molecular from King’s College London. , UK. “However, it was not known how the movement or function of fascin is controlled within the nucleus, and this hinders 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 a set of fascin “nanobodies” tagged with fluorescent markers, to alter its location in the cells. cells and explore their interactions with other proteins in the nucleus.
They found that fascin is actively transported in and out of the nucleus and, once there, 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 nucleus, called histones. When fascin is not involved in actin bundling, it is bound to histone H3, an important player involved in the organization of DNA within the nucleus.
Given the interaction of fascin with histones, the team analyzed whether fascin was also involved in the DNA repair processes of cancer cells, which helps them survive. They found that DNA repair was impaired in cells lacking fascin, indicating that the protein may be required 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 small appendages called filopodia, which promote invasion. So the team wanted to understand whether moving all the fascin to the nucleus would prevent fascin’s cytoplasmic function. As they predicted, in cells with enhanced nuclear fascin, the number of filopodia was significantly reduced because there was no fascin in the cytoplasm to support the assembly of these structures. The cells also invaded less in 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 bundles of stable actin in the nucleus that prevented them from proceeding through the cell cycle. Collectively, these results indicate that instead of trying to find ways to block fascin, forcing it all into the nucleus of cancer cells could stop them from growing and moving.
“Our study provides insight into a novel role for fascin in controlling nuclear actin bundling to support tumor cell viability,” concludes lead author Maddy Parsons, professor of cell biology at the Randall Center for Cell and Molecular Biophysics, King’s College London. “Since 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 the promotion of fascin accumulation in the nucleus of cancer cells, rather than instead of focusing only on targeting it to the cell cytoplasm, it could be an alternative approach that would prevent both tumor growth and spread.”
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