Delving into dark matter

NEW YORK—Non-coding RNA molecules in cancer cells set off an immune response, because they have features similar to pathogens, according to researchers at the Icahn School of Medicine at Mount Sinai. Because these molecules are expressed and amplified in cancer, the immune response they produce could influence the cancer’s growth, the investigators said in their article recently published in PNAS.

The researchers probed a part of the genome’s “dark matter,” an area known as satellite DNA, which produces large quantities of non-coding RNA (ncRNA) set apart from coding genes and mRNA. While these RNA molecules do not produce proteins, they may have important regulatory roles. Because of epigenetic alterations, tumors may transcribe ncRNAs that are silenced. Some of this RNA comes from the dark matter, which has elements not transcribed in normal tissue. The researchers wanted to explore the activation mechanism to improve immunotherapy outcomes.

The multinational team—including Roswell Park Institute in New York, Massachusetts General Hospital in Boston, the Centre National de la Recherche Scientifique and Ecole Normale Supérieure in Paris and the Institute for Advanced Study in Princeton, N.J.—used mathematical tools derived from theoretical physics to help understand ncRNA dark matter. The quantitative approach was taken from statistical physics and was used to characterize non-coding RNA transcribed by normal tissue as compared with non-coding RNA in tumors. The team found that in several cancers where odd RNAs were being activated and transcribed, these unusual RNAs were substantially amplified.

“While non-coding RNA in normal tissue displays patterns of motif usage consistent with that of coding RNA, the RNA transcribed in tumors, but rarely found in normal tissue, can have motif usage usually linked with viral and bacterial genomes,” the PNAS paper said.

According to the study’s senior investigator, Dr. Benjamin Greenbaum, an assistant professor at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, “These ncRNAs are found in both human and mice cancer cells. These areas were called ‘junk DNA,' but over the last five years, researchers have come to understand this is the home of a number of functionally important ncRNAs.”

As Dr. Nina Bhardwaj, director of immunotherapy and professor of hematology and medical oncology at The Tisch Cancer Institute and co-senior investigator on this research, added, “Cancer appears to use these ncRNAs to stimulate an immune response that could encourage tumor growth and survival, although much remains unknown about their role. If further research defines these molecules as helping cancer grow, it may be possible to either target and inhibit these molecules or use them as a marker to look for cancer development. On the other hand, research may show that they are mounting some sort of immune fight against cancer. In that case, we could try to boost that effort.”

Greenbaum, a computational biologist, explained, “We searched a large database of ncRNA for patterns of nucleotides that were unusual. Think of the genome’s sequence of nucleotides as words. In the human genome, some of the words are typically over- and under-represented. We wanted to know how these patterns differed in the RNA transcribed in cancers, such as those from satellite regions. The methods we used allowed us to analyze this big dataset much faster.”

Bhardwaj added, “The ncRNAs in cancers where odd RNAs were being activated and transcribed had unusual patterns that were similar to some pathogens, and this causes them to stimulate an innate immune response.”

“All in all, we believe these ncRNAs may play a significant role in mediating immune responses against cancer, but much work remains to describe their precise interactions,” said Greenbaum. “If we could characterize the ncRNA and link it with specific pathways, we could understand its role in the tumor environment and determine how it can be utilized for patient therapy.”