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Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy.
Wedge, Marie-Eve; Jennings, Victoria A; Crupi, Mathieu J F; Poutou, Joanna; Jamieson, Taylor; Pelin, Adrian; Pugliese, Giuseppe; de Souza, Christiano Tanese; Petryk, Julia; Laight, Brian J; Boileau, Meaghan; Taha, Zaid; Alluqmani, Nouf; McKay, Hayley E; Pikor, Larissa; Khan, Sarwat Tahsin; Azad, Taha; Rezaei, Reza; Austin, Bradley; He, Xiaohong; Mansfield, David; Rose, Elaine; Brown, Emily E F; Crawford, Natalie; Alkayyal, Almohanad; Surendran, Abera; Singaravelu, Ragunath; Roy, Dominic G; Migneco, Gemma; McSweeney, Benjamin; Cottee, Mary Lynn; Jacobus, Egon J; Keller, Brian A; Yamaguchi, Takafumi N; Boutros, Paul C; Geoffrion, Michele; Rayner, Katey J; Chatterjee, Avijit; Auer, Rebecca C; Diallo, Jean-Simon; Gibbings, Derrick; tenOever, Benjamin R; Melcher, Alan; Bell, John C; Ilkow, Carolina S.
Affiliation
  • Wedge ME; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Jennings VA; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
  • Crupi MJF; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Poutou J; Institute of Cancer Research, London, UK.
  • Jamieson T; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
  • Pelin A; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Pugliese G; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • de Souza CT; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Petryk J; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Laight BJ; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Boileau M; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Taha Z; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Alluqmani N; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • McKay HE; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Pikor L; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Khan ST; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Azad T; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Rezaei R; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Austin B; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • He X; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Mansfield D; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Rose E; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Brown EEF; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Crawford N; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Alkayyal A; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Surendran A; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Singaravelu R; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Roy DG; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Migneco G; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • McSweeney B; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Cottee ML; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Jacobus EJ; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Keller BA; Institute of Cancer Research, London, UK.
  • Yamaguchi TN; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Boutros PC; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Geoffrion M; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Rayner KJ; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Chatterjee A; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Auer RC; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.
  • Diallo JS; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Gibbings D; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • tenOever BR; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Melcher A; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
  • Bell JC; Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Ilkow CS; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Nat Commun ; 13(1): 1898, 2022 04 07.
Article in En | MEDLINE | ID: mdl-35393414
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: MicroRNAs / Oncolytic Viruses / Oncolytic Virotherapy / Extracellular Vesicles / Neoplasms Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Type: Article Affiliation country: Canada
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: MicroRNAs / Oncolytic Viruses / Oncolytic Virotherapy / Extracellular Vesicles / Neoplasms Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Type: Article Affiliation country: Canada