Reoviral Cytolysis is Modulated by Stemness
AdvisorJohnston, Randal N.
Rancourt, Derrick E.
AuthorBourhill, Tarryn Jackie
Committee MemberCobb, Jennifer A.
Mahoney, Douglas J.
oncolytic viral therapy
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AbstractOncolytic viruses (OVs) are an emerging cancer therapeutic that act by selectively targeting and lysing cancerous cells and by stimulating anti-tumour immune responses, while leaving normal cells mainly unaffected. Reovirus is a well-studied OV that received fast track designation and a special protocol assessment agreement from the FDA for the treatment of metastatic breast cancer. The mechanisms governing reoviral selectivity are not well characterised and are a topic of debate. Reovirus is capable of infecting and lysing cancer cells and, cancer stem cells, and here we demonstrate its ability to also infect and kill healthy pluripotent stem cells (PSCs). This has led us to hypothesize that pathways responsible for stemness modulate reoviral tropism. We find that reovirus is capable of killing murine and human embryonic and induced pluripotent stem cells. Differentiation of PSCs alters the cells’ reoviral-permissive state to a resistant one. In a cancer cell line that was resistant to reoviral oncolysis, induction of pluripotency programming renders these cells permissive to cytolysis. In light of the recent view that pluripotency induction shares similar pathways with carcinogenesis, the same subset of genes that are activated in cancer may also be up-regulated in PSCs (e.g. c-MYC), rendering PSCs permissive to infection. Bioinformatic analysis indicated that the Yamanaka factors may be involved in regulating reoviral selectivity, however this requires further experimental validation. Mechanistic insights from these studies will be useful for the advancement of reoviral oncolytic therapy.
CitationBourhill, T. J. (2020). Reoviral Cytolysis is Modulated by Stemness (Unpublished doctoral thesis). University of Calgary, Calgary, AB.
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