Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 04 2022
07 04 2022
Historique:
received:
11
11
2021
accepted:
07
03
2022
entrez:
8
4
2022
pubmed:
9
4
2022
medline:
12
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35393414
doi: 10.1038/s41467-022-29526-8
pii: 10.1038/s41467-022-29526-8
pmc: PMC8990073
doi:
Substances chimiques
MicroRNAs
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1898Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : CIHR
ID : 377104
Pays : Canada
Organisme : CIHR
ID : INI-147824
Pays : Canada
Organisme : Wellcome Trust
ID : 108466/Z/15/Z
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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