Researchers have finally linked the function of a specific domain of proteins important in plant and microbial biology to the trigger for human cancer, knowledge that had eluded scientists for decades.
The team’s findings, published in Nature Communications Biology, open a new way to develop selective drug therapies to fight different types of cancer, such as those that start in the breast and stomach.
The ORNL scientists set out to prove experimentally what they had first concluded with computational studies: that the plasminogen-apple-nematode domain, or PAN, is linked to cell proliferation that drives tumor growth in humans and defense signaling during plant interactions – microbe in bioenergy crops. The association was first made when researchers examined the genomes of crops such as poplar and willow.
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In the latest study, the ORNL team identified four essential amino acids, called cysteine residues in the HGF protein, that are critical for the function of the PAN domain, and studied their behavior in human cancer cell lines. They found that mutating any of these amino acids turns off a signaling pathway known as HGF-c-MET, which is abnormally elevated in cancer cells, causing them to multiply and spread rapidly.
Because cysteine residues are known to have many functions, the scientists randomly tested other cysteines in the protein and found that none of them had the same effect on shutting down HGF-c-MET signaling. Mutating the four key cysteines had no effect on the overall structure of the protein and only 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’s very difficult to design molecules that interact with an entire protein,” he said. “Knowing the specific amino acids to target in this protein is a big advance. You don’t have to go for all the protein; just look for these four specific residues.’
The identification of these essential residues is a testament to the predictive power the team has built at ORNL, using 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-editing tool.
The discovery could lead to treatments for other diseases, including disrupting the infection pathway in mosquitoes to make them less able to carry the malaria parasite and fighting the HLB virus killing citrus trees in Florida and California by targeting to 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 improve resistance to pathogens and pests in biomass crops, such as poplar and willow, that can be broken down and turned into sustainable jet fuel. They investigate the genetic processes that promote beneficial interactions between plants and microbes to build resilience in these crops.
The research demonstrates the close similarities in the DNA structure of plants, humans and other organisms, making plants an important platform for discovery, 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 with equal efficiency on plant and human cancers. The expertise is the same,” said Debjani Pal, an ORNL postdoctoral fellow 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 reproducible in all of them, no matter which cell line you reuse.”
“At the bottom of it all, we have the same biological basis,” Muchero said.