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 a new avenue 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 experimentally prove what they had first inferred from computational studies: that the plasminogen-apple nematode domain, or PAN, is linked to cell proliferation that drives tumor growth in and defense signaling during plant-microbe interactions in bioenergetic crops. The association was first made when researchers explored the genomes of crops like poplar and willow.
In the latest study, the ORNL team identified four central amino acids called cysteine residues in the HGF protein essential for the function of the PAN domain and studied their behavior in human cancer cell lines. They discovered that mutating one of these amino acids turned off the signaling pathway known as HGF-c-MET which is abnormally high 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 in the protein and found that none of them had the same impact on stopping HGF-c-MET signaling. Mutating the 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.
Disrupting 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 to interfere with an entire protein,” he said. “Knowing the specific amino acids to target in this protein is a big step forward. You don’t have to search for the entire protein; just search for those four specific residues.”
Identifying these core residues is 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 resources. supercomputing and CRISPR/CAS-9 gene editing tool.
The discovery could lead to treatments for other diseases, including disrupting mosquitoes’ infection pathway to make them less able to carry the malaria parasite, and fighting the HLB virus that kills citrus fruits in Florida and California. by targeting the Asian citrus psyllid insect that spreads it. .
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, which can be broken down and converted into sustainable jet fuel. They are exploring the genetic processes that encourage beneficial interactions between plants and microbes to enhance the hardiness of these crops.
The research demonstrates the close similarities in the DNA structure of plants, humans and other organisms, which make 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 effectiveness on plant and human cancers. The expertise is the same,” said Debjani Pal, a postdoctoral researcher at ORNL with a background in biochemistry and human cancer research. “We have established a globalized experimental platform here at ORNL that shows whatever system you use, plant or animal, if your hypothesis is correct, the science is reproducible in all of them, regardless of the cell line that you are using.”
“At the bottom of it all, we have the same biological underpinnings,” Muchero said.
Other team members from ORNL’s Biosciences Division include Kuntal De, Carly Shanks, Kai Feng, Timothy Yates, Jennifer Morrell-Falvey, Russell Davidson and Jerry Parks.
The plant research was supported by the Biological and Environmental Research Program of the DOE Office of Science. Funding directed by the ORNL lab supported work with human cell lines. The researchers used resources from the Oak Ridge Leadership Computing Facility, a DOE Office of Science user facility, as well as the ORNL Science Computing and Data Environment.
UT-Battelle operates the Oak Ridge National Laboratory for the DOE’s Office of Science, the largest support of basic physical science research in the United States. The DOE’s Office of Science works to address some of the most pressing challenges of our time. For more information, visit energy.gov/science.