Breaking free: Scientists show how telomeric RNA molecule escapes and produces inflammatory response

Now, a new study has found that TERRA can be found outside of cells and serve as a potentially important cell signaling molecule that induces an inflammatory response, and this activity may play an important role in the development of cancer.

The new findings, showing the first evidence of TERRA existing outside of cells, were published online by the Proceedings of the National Academy of Sciences.

Telomeres function very similarly to aglets, the plastic tips that are found on shoelaces. Like aglets, telomeres prevent chromosomes from "unraveling." Telomeres are made up of short segments of DNA, and as we get older, they gradually erode. Shortening of telomeres is linked to age-related diseases like cancer.

TERRA is an example of RNA that is found in telomeres. The traditional definition of RNA has it acting as an intermediate molecule that takes the coding from a DNA and translates that code into proteins for the cell. However, TERRA is a form of non-coding RNA that is transcribed from the telomere itself to create its own effects in the cell, like how the DNA of the cell is actually read.

In prior studies, researchers from Wistar and other institutions observed that when DNA in telomeres are lost, small proteins called inflammatory cytokines are secreted from the senescent cell. These proteins promote inflammation as a response to stress and are often a hallmark of several chronic illnesses. Wistar scientists wanted to know how telomere dysfunction was linked to this inflammatory behavior.

"Nucleic acid structures like TERRA can have powerful effects on immune pathways, and since we know there is a link between telomere dysfunction and inflammation, it made sense to study TERRA in much greater detail," said Zhuo Wang, a trainee in the laboratory of Paul Lieberman, Ph.D., at The Wistar Institute and first author of the study. "What we found was a completely new function of TERRA outside of telomeres that can provide us with more information as to how this molecule is linked to the development of certain types of cancer."

Wistar scientists found TERRA in the extracellular environment outside of the nucleus of the cells while looking for the molecule in a mouse model of medulloblastoma (a type of brain cancer) and a developing embryonic brain as well as human tissue cell culture lines. In blood plasma, TERRA was one of the most highly represented RNA molecules found in the circulating DNA outside of cells. The TERRA found outside of cells is actually shorter and more stable than those found inside the cells.

Why does this cell-free TERRA leave the cell in the first place? The researchers believe that it's performing a signaling function and specifically signaling that cellular stress or damage has occurred. This prompts the inflammatory response and the release of cytokines.

"This is the first time we've observed TERRA outside of cells, but it underscores our lab's previous research into this RNA molecule and its connection to aging and cancer," said Lieberman, professor and program leader of the Gene Expression and Regulation program, director of the Center for Chemical Biology and Translational Medicine, and the Hilary Koprowski, M.D., endowed professor at Wistar. "Shortened telomeres have been associated with inflammation, but now we have shown that telomeres directly or indirectly contribute to inflammatory signaling."

Lieberman said the next steps based on these findings involve assessing the impact of TERRA secretion on the tissue microenvironment and cancer development. They are already coordinating efforts with Jose Conejo-Garcia, M.D., Ph.D., professor and program leader of the Tumor Microenvironment and Metastasis program at Wistar, to use an ovarian cancer mouse model to study this question. They also plan to analyze tumor tissue samples from Wistar's collaborative partners at the Helen F. Graham Cancer of Christiana Health in Delaware to study how TERRA is correlated with cancer development. Additionally, Wistar is actively seeking partners interested in translating these novel discoveries into companion diagnostics for therapeutics targeting telomerase.