UVA Comprehensive Cancer Center researchers have found an answer to one of the great mysteries of human biology, and the discovery could have major implications for the battle against breast cancer and other diseases.
It's called the "G-value paradox:" Humans have no more protein-making genes than a tiny roundworm, yet somehow our bodies and brains are vastly more complex. Scientists have come up with various explanations for how this can be, but UVA's Hui Li, PhD, has identified an important and surprising contributor: "chimeric" RNA once thought to be cellular junk.
Li's new findings indicate these RNA molecules are far from useless debris. Instead, they can generate genetic instructions – expanding our cellular blueprints beyond our genes – and perform essential functions in healthy cells.
Further, Li and his team found that faulty chimeric RNA play an important role in the development of breast cancer. The researchers have developed an "atlas" mapping RNA chimeras in more than 1,000 cancer cell lines and found that the RNA was often malfunctioning in primary breast cancer tumors. They suspect that chimera problems are driving other cancers and diseases as well.
"We are getting better at finding chimeric RNAs, but we don't know if they are just noise or functional meaningful," said Li, of the University of Virginia School of Medicine's Department of Pathology. "The work has led to the discovery of a large number of functional chimeric RNAs, some of which may play important roles in cancer."
Understanding Chimeric RNA
In Greek mythology, the chimera was a fire-breathing monster that combined lion, goat and serpent. Similarly, chimeric RNA combines genetic material from two or more genes. Scientists first assumed these RNAs were just mistakes – genetic material Frankensteined together accidentally as cells carried out their programming – or possibly the result of cancer, which can be driven by faulty RNA.
Eventually scientists realized that chimeric RNA are common throughout all our tissues, and there was a growing acceptance that these were not mistakes but a normal part of our physiology. There was little understanding, however, of what individual chimeric RNAs might do or their importance in healthy cells.
To address this, Li and his team developed an analysis tool – a "prediction pipeline" – to predict and assess the function of chimeras. They then used this to create an atlas of more than 569,000 chimeric RNAs across 1,019 cancer cell lines.
It turned out the once-dismissed chimeras were essential in both good cellular health and disease. Eliminating the chimeras in healthy cells disrupted the normal cell cycle and caused harmful changes that reduced the cells' ability to survive. This has prompted Li to conclude that chimeric RNAs play a wide variety of critical roles in vital cellular processes. The results "demonstrate that chimeric RNAs constitute a previously underappreciated layer of gene expression, expanding the functional genome beyond conventional genetics," Li and his colleagues write in a new scientific paper.
Further, they found that chimeric RNA was often malfunctioning in primary breast cancer tumors. Doctors have already been able to develop important new cancer treatments by targeting specific cancer-causing chimeras, and Li's new atlas sets the stage to advance that approach dramatically by helping researchers understand what chimeras do and how they can be targeted to improve cancer care.
"We hope the broad scientific community can take advantage of the resource we generated and build on these findings for new discoveries and clinical applications," Li said. "We are only scratching the surface of this new biology. A lot of exciting discoveries lie ahead in the field. We encourage the next generation scientists to join the adventure."
Finding new ways to improve patient care is a core mission of both UVA Comprehensive Cancer Center and UVA's new Paul and Diane Manning Institute of Biotechnology. UVA Comprehensive Cancer Center is one of only 58 cancer centers in the country to earn the elite "comprehensive" designation from the National Cancer Institute in recognition of their exceptional patient care and cutting-edge cancer research.
The Manning Institute, meanwhile, has been launched to accelerate how quickly discoveries such as Li's can be translated into new drugs and treatments for cancer and other complex diseases, to benefit patients across Virginia and around the world.
Findings Published
Li and his colleagues have published their findings in the scientific journal Science Advances . The research team consisted of Samir Lalani, Samuel Haddox, Kendall Bromley, Shafaque Zahra, Marina Wang, Mason Ingram, Sehajroop Gadh, Shriya Gunalan, Sulun Ke, Qiong Wang, Fujun Qin, Eric Hendrickson, Anja Bielinsky and Li. The scientists have no financial interest in the work.
The research was supported by the National Institutes of Health's National Institute of General Medical Sciences, grants T32GM136615, T32GM139787 and R35GM141805; the National Cancer Institute, grants R01CA266524 and P30-CA044579; and a UVA Comprehensive Cancer Center Research Fellowship.
