Researchers at UHN reveal how a molecule known as circular RNA (circRNA) drives the transformation of specific prostate and lung cancers into more aggressive, treatment-resistant forms, highlighting new potential therapeutic targets.
Prostate and lung adenocarcinomas are cancers that form in glands that line these organs. Interference of gene regulatory programs in neurons can transform these cancers into more aggressive types: neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC), respectively.
Both NEPC and SCLC are neuroendocrine tumours, forming from neuroendocrine cells – nerve cells that also produce hormones. NEPC and SCLC are more difficult to treat and share similar genetic changes.
CircRNAs are a form of RNA, genetic material that generally does not produce proteins but instead helps regulate gene activity. Previous evidence has identified a link between circRNAs and the regulation of various biological processes important for cancer development.
However, their role in driving cancer transformation remains unexplored.
Through gene expression analysis, a research team from UHN's Princess Margaret Cancer Centre (PM) identified a specific circRNA, circRMST, which is highly active in NEPC and SCLC. They found that circRMST is essential for tumour growth and the expression of ASCL1 - a key regulator for turning a cell into a neuroendocrine cell.
Using genetic tools in experimental models, the research team found that circRMST is also essential for the transformation of adenocarcinoma into aggressive neuroendocrine tumour types. Further analysis revealed that circRMST interacts with two other key proteins, SOX2 and NKX2-1, to promote ASCL1 expression and drive the development of neuroendocrine cell characteristics.
This study, whose co-first authors include Dr. Mona Teng, a former doctoral student at PM, and Dr. Xin Xu, a postdoctoral researcher at PM, underscores the direct regulatory role of circRMST in the progression of prostate and lung adenocarcinoma.
By highlighting an essential player in the changes of these cancers, the findings reveal potential new insights into therapeutic strategies for targeting neuroendocrine tumours.
Dr. Housheng (Hansen) He, Senior Scientist at PM, Tier 1 Canada Research Chair in RNA Medicine, and professor in the Department of Medical Biophysics at the University of Toronto, is the lead corresponding author of the study.
This work was supported by the Canadian Institutes of Health Research, the Terry Fox Research Institute, the Marathon of Hope Cancer Centres Network, the Joey and Toby Tanenbaum/Brazilian Ball Chair in Prostate Cancer at Princess Margaret Cancer Centre, the Canada Foundation for Innovation, Cancer Research Society, National Institutes of Health/National Cancer Institute, the Clinical and Translational Science Center at Weill Cornell Medical Center, National Natural Science Foundation of China, Prostate Cancer Foundation (PCF) and the United States Department of Defense.
Co-author Dr. Benjamin Lok reports grants from Pfizer; and grants, personal fees, and non-financial support from AstraZeneca outside the submitted work.
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