Scientists discover cancer trigger that could spur targeted drug therapies

Researchers at the Department of Energy’s Oak Ridge National Laboratory have definitively linked the function of a specific domain of proteins important in plant-microbe biology to a cancer trigger in humans, knowledge that had eluded scientists for decades.

The team’s findings, published in Nature Communications Biology, open up a new avenue for the development of selective drug therapies to fight a variety of cancers such as those that begin in the breast and stomach.

ORNL scientists set out to prove experimentally what they first deduced with computational studies: that the plasminogen-apple-nematode, or PAN, domain is linked to the cell proliferation that drives tumor growth in humans and defense signaling during plant-microbe interactions in bioenergy crops. The association was first made as researchers explored the genomes of crops like poplar and willow.

In the latest study, the ORNL team pinpointed four core amino acids called cysteine residues in the HGF protein critical to the PAN domain’s function and studied their behavior in human cancer cell lines. They found that mutating any one of those amino acids turned off the signaling pathway known as HGF-c-MET that is abnormally heightened in cancer cells, causing them to rapidly multiply and spread.

Since cysteine residues are known to have many functions, the scientists also randomly tested other cysteines throughout the protein and found that none of them had the same impact on shutting down HGF-c-MET signaling. Mutating the four key cysteines had no effect on the overall structure of the protein, and merely inhibited the cancer signaling pathway, the team noted in the study.

Disrupting the right signal is one of the biggest challenges in developing new cancer therapies, said ORNL geneticist Wellington Muchero.

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