Wedge, Marie-Eve, Jennings, Victoria A orcid.org/0000-0003-1321-0333, Crupi, Mathieu J F et al. (42 more authors) (2022) Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy. Nature Communications. 1898. ISSN: 2041-1723
Abstract
Recent advances in cancer therapeutics clearly demonstrate the need for innovative multiplex therapies that attack the tumour on multiple fronts. Oncolytic or "cancer-killing" viruses (OVs) represent up-and-coming multi-mechanistic immunotherapeutic drugs for the treatment of cancer. In this study, we perform an in-vitro screen based on virus-encoded artificial microRNAs (amiRNAs) and find that a unique amiRNA, herein termed amiR-4, confers a replicative advantage to the VSVΔ51 OV platform. Target validation of amiR-4 reveals ARID1A, a protein involved in chromatin remodelling, as an important player in resistance to OV replication. Virus-directed targeting of ARID1A coupled with small-molecule inhibition of the methyltransferase EZH2 leads to the synthetic lethal killing of both infected and uninfected tumour cells. The bystander killing of uninfected cells is mediated by intercellular transfer of extracellular vesicles carrying amiR-4 cargo. Altogether, our findings establish that OVs can serve as replicating vehicles for amiRNA therapeutics with the potential for combination with small molecule and immune checkpoint inhibitor therapy.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2022. The Author(s). |
Keywords: | Extracellular Vesicles,Humans,MicroRNAs/genetics,Neoplasms/therapy,Oncolytic Virotherapy,Oncolytic Viruses/genetics |
Dates: |
|
Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) The University of York > Faculty of Sciences (York) > Biology (York) > Jack Birch Unit for Molecular Carcinogenesis (York) |
Depositing User: | Pure (York) |
Date Deposited: | 28 Aug 2025 15:30 |
Last Modified: | 28 Aug 2025 23:09 |
Published Version: | https://doi.org/10.1038/s41467-022-29526-8 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1038/s41467-022-29526-8 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:230913 |