New research detailing a specific domain of proteins that are important in plant-microbe biology have now been linked to a cancer trigger in humans, information that has eluded scientists for decades which could play a role in developing targeted therapies in breast and stomach cancers, among others. The findings, from investigators at the Department of Energy’s Oak Ridge National Laboratory (ORNL), were published in Nature Communications Biology.
The new research springs from computational studies published in 2019 that asserted 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. This association was first made by researchers exploring the genomes of crop like poplar and willow.
In the new study, the ORNL investigator identified 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.
While the study showed how disrupting the signaling can disrupt he growth of cancer, interrupting the right signal is one of the biggest challenges in developing new cancer therapies.
“It’s very difficult to engineer molecules to interfere with an entire protein,” said ORNL geneticist Wellington Muchero. “Knowing the specific amino acids to target within that protein is a big advancement. You don’t have to search the entire protein; just look for these four specific residues.”
The research demonstrates the close similarities in the DNA structure of plants, humans and other organisms, which make plants an important discovery platform, Muchero said. “We can do things with plants that you cannot do with humans or animals in the research process,” he added.
“I can work with equal efficiency in plant and human cancers. The expertise is the same,” said Debjani Pal, an ORNL postdoctoral researcher with a background in biochemistry and human cancer research. “We’ve established a globalized experimental platform here at ORNL that shows no matter what system you’re using, plant or animal, if your hypothesis is correct then the science is repeatable in all of them, no matter what cell line you’re using.”
As Muchero noted: “At the bottom of it all, we have the same biological underpinnings.”
