Genome's non-coding 'dark matter' plays role in cancer development

Genomic 'dark matter' has been suggested to play a role in the development of pancreatic cancer.

Researchers at Duke-NUS Medical School in Singapore systematically investigated the role of long non-coding RNAs (lncRNAs), which carry a large proportion of DNA that does not get translated into proteins. Previously thought to serve no function, the researchers showed that IncRNAs could play a role in pancreatic cancer. 

Lead author Shiyang Liu, from Duke-NUS Medical School said: 'By combining several advanced tools, we were able to investigate the role and function of "the dark matter that matters" in pancreatic cancer.'

'Wnt signalling' is a well-established cellular pathway that can fuel the growth and progression of several cancers, including some pancreatic cancers. While it is clear that Wnt regulates many genes that are involved in cancer growth, it is less clear what influence Wnt signalling has on lncRNAs.  

To find out more about the effect of Wnt signalling on lncRNAs, the researchers used ETC-159, a drug that works by inhibiting Wnt signalling and that is currently used in clinical trials for certain colorectal and gynaecological cancers. By inhibiting Wnt signalling in both a mouse model of pancreatic cancer and pancreatic cancer cells, the researchers were able to measure the effect the inhibition had on lncRNAs.

They identified 3633 lncRNAs, of which 1503 were affected by Wnt signalling in a pancreatic cancer mouse model. The lncRNAs were much more sensitive to changes in Wnt signalling in the mouse model than they were in the pancreatic cancer cells cultured in the lab. Using CRISPR-based genome editing, the researchers were able to turn off the Wnt-regulated lncRNAs in the mouse model and in the cancer cell culture. Of the 1503 Wnt-regulated lncRNAs, 13 (one percent) had an effect on cancer cell growth in the cultured cells. Almost twice as many, (25) had an effect on cancer cell growth in the mouse model – highlighting the effect the choice of model organism can have on a study.

Dr David Virshup, director of Duke-NUS's Cancer and Stem Cell Biology Programme and senior co-author of the study said: 'Our study provides a unique window in the largely unknown role of the dark matter of the genome that plays a functional role in pancreatic cancer, and will be a valuable resource for the scientific community studying Wnt-regulated lncRNAs in cancer. Understanding that a subset of Wnt-regulated lncRNAs can act as mediators of the oncogenic function of Wnt signalling in cancers provides potential new targets for precision cancer therapies.'