A recent study published in the Journal of Clinical Investigation found that certain cancer-causing proteins can switch on parts of a person’s genetic material that were previously inactive, potentially contributing to the development and progression of Ewing sarcoma and prostate cancer. This finding helps researchers understand why the environment around a tumour may cause inflammation and suppress the immune system, which can make it challenging to successfully treat solid tumours with immunotherapy. 

Along with his collaborators, Dr. Poul Sorensen, a distinguished scientist at the BC Cancer Research Institute and Professor of Pathology at the University of British Columbia and corresponding author of the study, identified that specific proteins, namely EWS-FLI1 and EWS-ERG in Ewing sarcoma and TMPRSS2-ERG or overexpressed ERG in prostate carcinoma, which are members of the ETS transcription factor family of proteins that control the activity of diverse genes, are key players in this process.

The study demonstrates that these cancer-causing proteins can bind to and reactivate heterochromatin, which are sequences of DNA that are normally inactive, and activate expression of certain RNAs in these areas. In particular, the researchers found Ewing sarcoma and prostate carcinoma tumour cells to have increased levels of two specific types of RNA, called HSAT2 and HSAT3, which are then packaged into small units called extracellular vesicles (EVs) and released into the tumour microenvironment. 

This process can lead to suppression of the immune system, as the EVs then interact with non-cancerous cells, including immune cells, which can activate signals that cause inflammation, DNA damage and disruption of cell division processes to cause immunosuppression. The team discovered that following this interaction, immune cells and other normal cells begin to release their own EVs containing similar RNAs, further amplifying the immunosuppressive environment. This process resembles how a virus infects cells, suggesting that tumour cells may use similar tactics to mimic viral infections. 

Additionally, the research team detected HSAT2 and HSAT3 and other repeat-derived RNAs, which are produced from repetitive sequences within the genome, in the blood of Ewing sarcoma patients and even more so in patients with metastatic disease. This suggests that monitoring levels of HSAT2 and HSAT3 in the blood and preventing their spread could help improve both treatments and diagnostic tests that use blood samples.

“This study shows the power of collaborative science, allowing us to uncover a really complex process showing how tumour cells exploit ancient biology to their advantage, which we can then hopefully use for diagnostic and therapeutic purposes,” said Dr. Sorensen.

Ewing sarcoma is a rare type of cancer that primarily affects the bones or soft tissues, and usually occurs in children and young adults. Prostate carcinoma, one of the most common types of cancer in BC, develops in the tissues of the prostate gland. 

Along with Dr. Sorensen, the team included international researchers from the University of Toronto, Technical University of Munich, and the Vancouver Prostate Centre. 

This work was made possible in part through grant funding from the BC Cancer Foundation.

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