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MicroRNA-based Regulation of Picornavirus Tropism
Published on: February 6, 2017
Modulation of Reoviral Cytolysis (II): Cellular Stemness
Tarryn Bourhill1, Leili Rohani1, Mehul Kumar1
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Abstract:
Oncolytic viruses (OVs) are an emerging cancer therapeutic that are intended to 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 is undergoing advanced clinical trials and has received FDA approval in selected circumstances. However, the mechanisms governing reoviral selectivity are not well characterised despite many years of effort, including those in our accompanying paper where we characterize pathways that do not consistently modulate reoviral cytolysis. We have earlier shown that reovirus is capable of infecting and lysing both certain types of cancer cells and also cancer stem cells, and here we demonstrate its ability to also infect and kill healthy pluripotent stem cells (PSCs). This led us to hypothesize that pathways responsible for stemness may constitute a novel route for the modulation of reoviral tropism. We find that reovirus is capable of killing both murine and human embryonic and induced pluripotent stem cells. Differentiation of PSCs alters the cells' reoviral-permissive state to a resistant one. In a breast cancer cell line that was resistant to reoviral oncolysis, induction of pluripotency programming rendered the cells permissive to cytolysis. Bioinformatic analysis indicates that expression of the Yamanaka pluripotency factors may be associated with regulating reoviral selectivity. Mechanistic insights from these studies will be useful for the advancement of reoviral oncolytic therapy.
Insights
Pluripotency pathways, not previously understood, influence how oncolytic viruses (OVs) like reovirus target cancer cells. Stemness reprogramming can make resistant cancer cells susceptible to reovirus therapy.
Area of Science:
- Oncolytic virology
- Cancer stem cell biology
- Stem cell biology
Background:
- Oncolytic viruses (OVs) offer a promising cancer therapy by selectively destroying cancer cells and stimulating anti-tumor immunity.
- Reovirus is a well-studied OV in advanced clinical trials, but the mechanisms of its selectivity remain unclear.
- Previous studies showed reovirus infects cancer cells and cancer stem cells, but its interaction with healthy stem cells was unknown.
Purpose of the Study:
- To investigate the role of stemness pathways in modulating the tropism and selectivity of reovirus.
- To determine if pluripotent stem cells (PSCs) are susceptible to reovirus infection and lysis.
- To explore the potential of reprogramming cancer cells to enhance their susceptibility to oncolytic virotherapy.
Main Methods:
- Infection and lysis assays on murine and human embryonic and induced pluripotent stem cells (PSCs).
- Assessment of reovirus susceptibility in PSCs upon differentiation.
- Reprogramming of a reovirus-resistant breast cancer cell line to pluripotency and subsequent evaluation of reovirus sensitivity.
- Bioinformatic analysis of Yamanaka factor expression in relation to reovirus selectivity.
Main Results:
- Reovirus effectively infects and lyses both murine and human embryonic and induced pluripotent stem cells (PSCs).
- Differentiation of PSCs renders them resistant to reovirus-mediated lysis.
- Inducing pluripotency in a resistant breast cancer cell line made it susceptible to reovirus oncolysis.
- Bioinformatic analysis suggests a correlation between Yamanaka pluripotency factors and reovirus selectivity.
Conclusions:
- Stemness pathways are a novel determinant of reoviral tropism and selectivity.
- Reovirus can infect and lyse healthy pluripotent stem cells, highlighting the need for precise targeting strategies.
- Reprogramming cancer cells towards pluripotency can overcome resistance to oncolytic virotherapy, offering new therapeutic avenues.
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