Can science pinpoint the triggers of certain cancers in humans?

The researchers definitively linked the function of a protein-specific domain important in plant microbial biology to cancer triggers in humans, knowledge that scientists have avoided for decades.

Team findings, published in natural Communication Biology, opens new avenues for the development of selective drug therapies to fight various types of cancer, such as cancers that start in the breast and stomach.

ORNL scientists set out to experimentally prove what they first concluded with a computational study: that the plasminogen-apple-nematode, or PAN, domain is associated with cell proliferation that promotes tumor growth in humans and defense signaling during plant-microbial interactions in plant-bioenergy. plant. This association was first made when researchers were exploring the genomes of plants such as poplars and willows.

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In the latest study, the ORNL team demonstrated four core amino acids called cysteine ​​residues in the HGF protein that are important for PAN domain function and studied their behavior in human cancer cell lines. They found that mutations in one of these amino acids shut down a signaling pathway known as HGF-c-MET, which is abnormally elevated in cancer cells, causing them to multiply and spread rapidly.

Since cysteine ​​residues are known to have multiple functions, the scientists also randomly tested other cysteine ​​​​in the whole protein and found that none of them had the same impact on turning off the HGF-c-MET signal. Mutations of four key cysteine ​​​​have no effect on the overall structure of the protein and only inhibit cancer signaling pathways, the team noted in the study.

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

“It’s very difficult to engineer a molecule to interfere with the whole protein,” he said. “Knowing the specific amino acid targeted in that protein is a major advance. You don’t need to search the entire protein; just look for these four specific residues.”

The identification of these core residues is a testament to the predictive power the team at ORNL has built, leveraging the lab’s expertise in plant biology and biochemistry, genetics, and computational biology, as well as its supercomputer resources and CRISPR/CAS-9 gene-editing tool.

The discovery could lead to treatments for other diseases, including interfering with the infection pathways in mosquitoes to make them less capable of carrying the malaria parasite and fighting the HLB virus, killing citrus trees in Florida and California by targeting the Asian citrus psyllid insect that spreads it. .

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In plants, ORNL scientists are using their knowledge of the PAN domain to increase resistance to pathogens and pests in plant biomass, such as poplar and willow, which can be broken down and converted into sustainable jet fuel. They explored the genetic processes that drive beneficial interactions between plants and microbes to build resistance in those plants.

The research demonstrates the close similarities in the DNA structure of plants, humans and other organisms, which makes plants an important discovery platform, Muchero said. “We can do things with plants that we can’t do with humans or animals in the research process,” he added.

“I can work with the same efficiency on plant and human cancers. The skills are the same,” said Debjani Pal, an ORNL postdoctoral researcher with a background in human cancer and biochemistry research. “We’ve set up a global experimental platform here at ORNL that shows it doesn’t matter what system you use, plant or animal, if your hypothesis is correct, then science can be repeated in all of them, no matter what cell line you’re reusing.”

“Basically, we have the same biological basis,” said Muchero.

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