Reoviral Cytolysis is Modulated by Stemness

Bourhill, Tarryn Jackie

Reoviral Cytolysis is Modulated by Stemness

dc.contributor.advisor	Johnston, Randal N.
dc.contributor.advisor	Rancourt, Derrick E.
dc.contributor.author	Bourhill, Tarryn Jackie
dc.contributor.committeemember	Cobb, Jennifer A.
dc.contributor.committeemember	Mahoney, Douglas J.
dc.date	2020-11
dc.date.accessioned	2020-10-15T18:12:14Z
dc.date.available	2020-10-15T18:12:14Z
dc.date.issued	2020-10-13
dc.description.abstract	Oncolytic 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.	en_US
dc.identifier.citation	Bourhill, T. J. (2020). Reoviral Cytolysis is Modulated by Stemness (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.	en_US
dc.identifier.doi	http://dx.doi.org/10.11575/PRISM/38336
dc.identifier.uri	http://hdl.handle.net/1880/112687
dc.language.iso	eng	en_US
dc.publisher.faculty	Cumming School of Medicine	en_US
dc.publisher.institution	University of Calgary	en
dc.rights	University 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.	en_US
dc.subject	Reovirus	en_US
dc.subject	oncolytic viral therapy	en_US
dc.subject	stemness	en_US
dc.subject	pluripotency	en_US
dc.subject	reprogramming	en_US
dc.subject	differentiation	en_US
dc.subject.classification	Biology--Cell	en_US
dc.subject.classification	Biology--Molecular	en_US
dc.subject.classification	Virology	en_US
dc.subject.classification	Oncology	en_US
dc.title	Reoviral Cytolysis is Modulated by Stemness	en_US
dc.type	doctoral thesis	en_US
thesis.degree.discipline	Medicine – Biochemistry and Molecular Biology	en_US
thesis.degree.grantor	University of Calgary	en_US
thesis.degree.name	Doctor of Philosophy (PhD)	en_US
ucalgary.item.requestcopy	true	en_US