Johnston, Randal N.Rancourt, Derrick E.Bourhill, Tarryn Jackie2020-10-152020-10-152020-10-13Bourhill, T. J. (2020). Reoviral Cytolysis is Modulated by Stemness (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.http://hdl.handle.net/1880/112687Oncolytic 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.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.Reovirusoncolytic viral therapystemnesspluripotencyreprogrammingdifferentiationBiology--CellBiology--MolecularVirologyOncologydoctoral thesis10.11575/PRISM/38336