Can science determine the cause of some types of cancer in humans?

Researchers have finally linked the function of a specific protein domain important in plant microbial biology to a cause of human cancer, knowledge that had eluded scientists for decades.

The team’s findings, published in Nature Communications Biology, pave the way for the development of selective drug therapies to fight a variety of cancers, such as those that start in the breast and stomach.

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

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

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. Mutation of four key cysteines had no effect on the overall structure of the protein and simply inhibited the cancer signaling pathway, the team noted in the study.

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

“It is very difficult to create molecules to interfere with an entire protein,” he said. “Knowing the specific amino acids to target within that protein is a huge advance. You don’t have to search the entire protein; you just search for these four specific residues.”

Identifying those essential residues is a testament to the predictive power the team has built at ORNL, leveraging the lab’s expertise in plant biology and biochemistry, genetics and computational biology, as well as its supercomputing resources and the CRISPR/CAS-9 gene-tool editing.

The discovery could lead to treatments for other diseases, including interrupting the infection pathway in mosquitoes to make them less able to carry the malaria parasite and combat the HLB virus, which is killing citrus trees in Florida and California targeting the Asian citrus psyllid bug that spreads it. .

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In plants, ORNL scientists are using their knowledge of the PAN domain to improve pathogen and pest resistance in biomass crops, such as poplar and willow, that can be broken down and converted into sustainable jet fuel. They are exploring the genetic processes that drive beneficial interactions between plants and microbes to create resilience in those crops.

The research shows 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 can’t do with humans or animals in the research process,” he added.

“I can work equally efficiently on plant and human cancer. The expertise is the same,” said Debjani Pal, an ORNL postdoctoral researcher with a background in biochemistry and human cancer research. “We’ve created 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 replicable across all of them, no matter what cell line you have.” Im using.”

“At the end of it all, we have the same biological foundations,” Muchero said.

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