Human Genome ‘Dark Matter’ Uncovers New Cancer Treatment — ScienceDaily

dark matter in the genome

As new targets, they focused on a poorly understood class of genes called ‘long noncoding RNAs’ (lncRNAs). LncRNAs are abundant in the so-called ‘dark matter’ or non-protein-coding DNA that makes up most of our genome. Although the human genome contains approximately 20,000 ‘classical’ protein-coding genes, this number is small compared to 100,000 lncRNAs. The biological function of 99% of lncRNAs is unknown.

As the name long noncoding RNA suggests, unlike messenger RNAs (mRNAs), they do not encode protein building plans. Like mRNA, lncRNA’s assembly instructions are contained in the cell’s DNA.

New tool determines potential targets

To study the role of lncRNAs in NSCLC, researchers began by analyzing publicly available datasets to find out which lncRNAs are present in NSCLC. This analysis yielded a list of over 800 lnRNAs that researchers wanted to explore for their importance to NSCLC cells. For this investigation, they developed a screening system that prevented the generation of selected lncRNAs by deleting some of the DNA’s construction instructions.

They applied the screening system to two patient-derived NSCLC cell lines and examined how inhibition of selected lncRNAs affected so-called ‘characteristics’ of cancer cells. Cellular behaviors that contribute to disease progression: proliferation, metastasis formation, and therapy resistance. “The advantage of assessing three different cancer signatures is that not only do we have a comprehensive view, but we also need to derive a single list of long non-coding RNAS that are important for non-small cell lung cancer across different experiments.” We also have a fair amount of data from , ”said Rory Johnson, assistant professor at the University of Bern, who led the NCCR RNA & Disease-funded project. The analysis ultimately yielded a list of 80 high-confidence candidate lncRNAs important for NSCLC out of over 800 surveyed. From these 80, researchers singled out several lncRNAs for follow-up experiments.

Break down long RNA with short RNA

These follow-up experiments used an approach that does not work at the DNA level and targets post-production lncRNAs. For this purpose, researchers used small chemically synthesized RNAs called antisense oligonucleotides (ASOs). Of note, several ASOs have been approved for the treatment of human disease, but her ASO for cancer has not yet been approved.

These follow-up experiments showed that for most of the selected lnRNAs, their disruption by ASO inhibited cancer cell division in cell culture. Importantly, the same treatments had little, if any, effect on non-cancerous lung cells, which should not be harmed by cancer treatments. In a three-dimensional model of NSCLC, inhibition of a single lncRNA by ASO reduced tumor growth by more than half. Taisia ​​Polidori, her co-first author, who worked on the project as part of her doctoral thesis research at the University of Bern, said, “It was interesting to see how well her antisense oligonucleotides could suppress tumor growth in different models. , we were very surprised.”

Therapeutic development and application to other tumor types

Researchers continue to work in preclinical cancer models and are considering working with established companies or creating startups to develop drugs to treat patients. . Regarding other cancers, co-first author and postdoctoral fellow at the University of Bern, Roberta Esposito, said: other cancer types. Dr. Esposito plans to use the ‘telescope’ to identify new targets in colorectal cancer. To this end, she receives funding from the University of Bern Medical School donated by Beatrice Ederer her Weber Foundation.

NCCR RNA and disease — the role of RNA in disease mechanisms

NCCRMore RNA and disease — the role of RNA biology in disease mechanisms I study RNA (ribonucleic acid), one of the very important classes of molecules of life. RNA (ribonucleic acid) is crucial to many important processes and is functionally much more complex than originally thought. For example, RNA defines the conditions under which a particular gene is activated or not activated within a particular cell. Any part of this gene regulation process that goes wrong or doesn’t run smoothly can lead to heart disease, cancer, brain disease, and metabolic disorders. NCCR brings together Swiss research groups studying different aspects of RNA biology. NCCR discovers new therapeutic targets by studying which regulatory mechanisms are dysregulated in disease. The lead institution is the University of Bern, co-led by ETH Zurich. The National Center for Research Competence is a research institute of the Swiss National Science Foundation (SNSF).