Discovery of pro-metastasis protein reveals mysterious link to neurodegeneration

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Researchers have identified a protein that makes breast cancer cells more likely to metastasize. What’s more, the protein appears to trigger cancer’s spread in part by blocking two other proteins normally linked to neurodegeneration, a finding that suggests a tie between two of the most common diseases of old age.

In work published earlier this month in Nature, they identify a protein that appears to act as a “master regulator” by blocking tumor suppressor genes and so helping to set metastasis in motion.

Although the research is in its very early days, if we learn more about how this process works, we may in the future be able to generate drugs that block the triggering of metastatic disease,” says Sohail Tavazoie, senior author on the study, Leon Hess Assistant Professor, and head of the Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology.

Aiding the spread: To confirm that the protein TARBP2 promotes metastasis, the researchers silenced this protein in metastatic breast cancer cells. They found that mice injected with these cells developed much less metastasis, shown as dark spots in lung tissue (top), than mice injected with cells containing normal levels of TARBP2 (bottom).

To pinpoint this protein, Tavazoie and his colleagues used a computer algorithm previously developed by first author Hani Goodarzi and co-author Saeed Tavazoie, a professor at Columbia University, to scan both the sequence and shape of RNA molecules in breast cancer cells. Only recently have cancer researchers begun to systematically look at the shapes of messenger RNA molecules, which encode instructions from DNA. It turns out that RNA shape matters because certain shapes offer binding sites for proteins that, once bound, determine the fate of the RNA molecule. These fates can include targeting the RNA molecules for destruction, an act that reduces expression of a gene.

Based on patterns they found in breast cancer cells prone to metastasis, including an unusual abundance of hairpin-like loops within the RNAs targeted for destruction, the researchers homed in on the hairpin-loop binding protein TARBP2.

In the cancer cells, the researchers concluded TARBP2 appears to act as a sort of master regulator by binding to multiple sites on RNA molecules and causing a suite of changes that lead to metastasis, including the destruction of RNAs. By destroying these RNAs, this protein can interfere with the expression of genes, and that appears to be TARBP2’s effect on some metastasis suppressing genes.

Indeed, they found TARBP2 is overexpressed in cells prone to metastasizing, as well as in metastatic human breast tumors themselves. When the researchers looked to see what genes might be turned down in these same cells, they found two surprises: APP, responsible for a protein linked to Alzheimer’s disease, and ZNF395, which is associated with Huntington’s disease.

In follow-up experiments, the researchers discovered ZNF395 appears to decrease the expression of genes linked to cancer, while a protein segment of APP directly inhibits breast cancer’s ability to metastasize. It turns out TARBP2 tunes down the expression of both of these metastasis suppressor genes; cells prone to metastasis showed higher levels of TARBP2 and lower levels of APP and ZNF395. In cancer cells that tend not to spread throughout the body, the opposite was true.

“This was a surprising finding, because these genes normally associated with neurodegeneration are now implicated in breast cancer metastasis and progression,” Tavazoie says. “It’s interesting that these totally disparate disease processes have a potential molecular link. We don’t know what that means yet.”

The study raises hopes of future therapeutic approaches that target master regulators, such as TARBP2, that bind RNAs. “If we can understand the mechanism by which TARBP2 interacts with RNA, maybe in the future we could generate small molecules that prevent it from sitting on RNA structures and shutting down the genes that suppress cancer progression,” Tavazoie says.

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