Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy.
Marie-Eve WedgeVictoria A JenningsMathieu J F CrupiJoanna PoutouTaylor R JamiesonAdrian PelinGiuseppe PuglieseChristiano Tanese de SouzaJulia PetrykBrian J LaightMeaghan BoileauZaid TahaNouf AlluqmaniHayley E McKayLarissa PikorSarwat Tahsin KhanTaha AzadReza RezaeiBradley AustinXiaohong HeDavid MansfieldElaine RoseEmily E F BrownNatalie CrawfordAlmohanad AlkayyalAbera SurendranRagunath SingaraveluDominic Guy RoyGemma MignecoBenjamin McSweeneyMary Lynn CotteeEgon J JacobusBrian A KellerTakafumi N YamaguchiPaul C BoutrosMichele GeoffrionKatey J RaynerAvijit ChatterjeeRebecca C AuerJean-Simon DialloDerrick GibbingsBenjamin R tenOeverAlan MelcherJohn Cameron BellCarolina S IlkowPublished in: Nature communications (2022)
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.
Keyphrases
- small molecule
- protein protein
- papillary thyroid
- induced apoptosis
- squamous cell
- high throughput
- cell cycle arrest
- hiv infected
- gene expression
- transcription factor
- dna damage
- stem cells
- cell death
- squamous cell carcinoma
- risk assessment
- bone marrow
- childhood cancer
- mesenchymal stem cells
- drug delivery
- smoking cessation
- combination therapy
- human health
- young adults