Unravelling the role of long noncoding RNAs in genome stability and cancer

Dr Lovorka Stojic, Group Leader in the Centre for Cancer Cell & Molecular Biology at Barts Cancer Institute (BCI), Queen Mary University of London, has recently received a Cancer Research UK (CRUK) Career Establishment Award. The award of approximately £990,000 will support a postdoctoral researcher and technician in Dr Stojic’s laboratory group for a period of 6 years to conduct a project on the role of long noncoding RNAs (lncRNAs) in the maintenance of genome stability and in cancer.

Genome instability, a feature of almost all cancers, is the increased tendency of the genetic information within cells to change during cell division. Genome instability contributes to genetic variation within tumours, driving cancer evolution and contributing to drug resistance. Until now, research has focused on the role of protein networks in the maintenance of genome stability but little is known about the contribution of RNA-based mechanisms.

RNA is an important biological molecule that carries messenger instructions from the genome required for the production of proteins in cells. However, one of the surprising discoveries of the postgenomic era is that only about 2% of the human genome codes for proteins; that means that the majority of the human genome is transcribed into thousands of noncoding RNAs (ncRNAs) that do not require translation into proteins, yet have important cellular functions.

Dr Stojic’s group is interested in understanding how one class of these ncRNAs, namely lncRNAs, control genome stability and how dysregulation of lncRNA-regulatory networks contribute to cancer.

Investigating new mechanisms involved in genome instability

Dr Stojic said:

“Despite functional characterisation of a handful of lncRNAs, our understanding of how lncRNAs regulate fundamental cellular processes and how lncRNAs are deregulated in cancer is still limited.”

“This CRUK award will allow my team to investigate new mechanisms involved in genome instability in cancer based on the alteration of lncRNAs. Our ultimate goal is to provide the foundation for innovative diagnostic and therapeutic modalities based on lncRNAs to improve the way we diagnose and treat cancer.”

Using multiple and complementary approaches ranging from cell biology assays to powerful “omics” approaches, the team will dissect the mechanisms used by lncRNAs to regulate genome stability and identify new lncRNAs that exhibit altered expression in cancer. The research will use clear cell renal cell carcinoma (ccRCC; the most common type of kidney cancer in adults) as a model system to investigate the significance of lncRNAs in cancer.

A collaborative approach

To execute this project, Dr Stojic has teamed up with several basic and clinical scientists in the UK and abroad. At the BCI, Dr Stojic’s team will be working closely with Dr Jun Wang, Dr Sarah McClelland and Dr Faraz Mardakheh, whose expertise in genomics and proteomics will help to identify mechanisms underlying the role of lncRNAs in genome stability. In collaboration with Professor Igor Ulitsky (Weizmann Institute of Science, Israel) the team will also explore conserved sequence elements within lncRNAs that may be involved in the maintenance of genome stability.

In order to maximise the clinical significance of this research for human disease, Dr Stojic has also established links with several clinicians including Professor Grant Stewart (Addenbroke’s Hospital, University of Cambridge) and Professor Thomas Powles (Centre for Experimental Cancer Medicine, BCI)  who will provide ccRCC tissue samples and valuable disease-specific clinical input.

With RNA-based approaches representing an expanding class of therapeutics, Dr Stojic and her team hope that this work may pave the way for the development of new RNA-based strategies to improve diagnosis and treatment of cancer.