Researchers at the Department of Energy’s Oak Ridge National Laboratory have finally linked the function of a specific protein domain important to plant-microbial biology to the trigger for human cancer, knowledge that has 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 sought to prove experimentally what they first concluded with computational studies: that the plasminogen-apple-nematode domain, or PAN, is linked to the cell proliferation that drives tumor growth in humans and defense signals during plant-plant interactions. microbe in bioenergy crops. The association was first made when researchers examined the genomes of crops such as poplar and willow.
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 search the whole 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 interrupting the infection pathway in mosquitoes to make them less able to transmit the malaria parasite and combating the HLB virus that is killing citrus trees 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, 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 what cell line you’re using.”
“At the bottom of it all, we have the same biological basis,” Muchero said.
Other team members in the ORNL Biosciences Division include Kuntal De, Carly Shanks, Kai Feng, Timothy Yates, Jennifer Morrell-Falvey, Russell Davidson, and Jerry Parks.
Plant research was supported by the DOE Office of Science Biological and Environmental Research Program. Laboratory-directed ORNL funding supported work with human cell lines. The researchers used resources at the Oak Ridge Leadership Computing Facility, a user facility of the DOE Office of Science, as well as the Compute and Data Environment for Science at ORNL.
UT-Battelle operates Oak Ridge National Laboratory for DOE’s Office of Science, the largest supporter of basic research in the physical sciences in the United States. DOE’s Office of Science works to address some of the most pressing challenges of our time. For more information, visit energy.gov/science.