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Newly discovered behavior in cancer cells signals dangerous metastasis

The researchers discovered this transition in cancer cells when they observed an error in "alternative splicing," a key element of the genetic copying program inside cells. Alternative splicing determines how the DNA is chopped into pieces and then reassembled. The order in which DNA is reassembled determines which proteins the gene produces.

In cancer cells, the splicing machinery goes awry -- as do myriad functions within the cells. When the splicing process proceeds one way, the cells become mesenchymal. Spliced another way, the cells turn epithelial.

To determine which way a cancer cell would turn, the scientists constructed a fluorescent "reporter" -- a protein that illuminates if the cell turns epithelial but lies dormant if the cell reverts to mesenchymal state.

By following the reporter's illumination within cancer cells in rats, the team viewed the very process of alternative splicing as it occurred in the tumors. The researchers were able to visualize specific portions of DNA, called exons, to see if they were included or excluded in the splicing process as the cell transformed.

"We found that the regulation of alternative splicing is different in mesenchymal versus epithelial cells," Garcia-Blanco said. "A particular exon, FGFR2 IIIc, is silenced in mesenchymal cells but is active in epithelial cells.

"We can visualize the genes as they are dynamically changing," he said. "We can define the cell types by observing their splicing patterns."

According to Garcia-Blanco, the cellular switch that is believed to guide the regulation of splicing is a protein called Fox. Both mesenchymal and epithelial cells produce Fox, but the protein is active only in epithelial cells, Garcia-Blanco said.

Fox also may have an accomplice or "co-factor" in or around epithelial cells that prompts it to activate, the researchers said. They speculate that this co-factor could be activated by contact with stroma --the suppor
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Source:Duke University Medical Center


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