Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy

Marie-Eve Wedge, Victoria A. Jennings, Mathieu J. F. Crupi, Joanna Poutou, Taylor Jamieson, Adrian Pelin, Giuseppe Pugliese, Christiano Tanese Souza, Julia Petryk, Brian J. Laight, Meaghan Boileau, Zaid Taha, Nouf Alluqmani, Hayley E. McKay, Larissa Pikor, Sarwat Tahsin Khan, Taha Azad, Reza Rezaei, Bradley Austin, Xiaohong He, David Mansfield, Elaine Rose, Emily E. F. Brown, Natalie Crawford, Almohanad Alkayyal, Abera Surendran, Ragunath Singaravelu, Dominic G. Roy, Gemma Migneco, Benjamin McSweeney, Mary Lynn Cottee, Egon J. Jacobus, Brian A. Keller, Takafumi N. Yamaguchi, Paul C. Boutros, Michele Geoffrion, Katey J. Rayner, Avijit Chatterjee, Rebecca C. Auer, Jean-Simon Diallo, Derrick Gibbings, Benjamin R. tenOever, Alan Melcher, John C. Bell and Carolina S. Ilkow ()
Additional contact information
Marie-Eve Wedge: Ottawa Hospital Research Institute
Victoria A. Jennings: Ottawa Hospital Research Institute
Mathieu J. F. Crupi: Ottawa Hospital Research Institute
Joanna Poutou: Ottawa Hospital Research Institute
Taylor Jamieson: Ottawa Hospital Research Institute
Adrian Pelin: Ottawa Hospital Research Institute
Giuseppe Pugliese: Ottawa Hospital Research Institute
Christiano Tanese Souza: Ottawa Hospital Research Institute
Julia Petryk: Ottawa Hospital Research Institute
Brian J. Laight: Ottawa Hospital Research Institute
Meaghan Boileau: Ottawa Hospital Research Institute
Zaid Taha: Ottawa Hospital Research Institute
Nouf Alluqmani: Ottawa Hospital Research Institute
Hayley E. McKay: Ottawa Hospital Research Institute
Larissa Pikor: Ottawa Hospital Research Institute
Sarwat Tahsin Khan: Ottawa Hospital Research Institute
Taha Azad: Ottawa Hospital Research Institute
Reza Rezaei: Ottawa Hospital Research Institute
Bradley Austin: Ottawa Hospital Research Institute
Xiaohong He: Ottawa Hospital Research Institute
David Mansfield: Institute of Cancer Research
Elaine Rose: Ottawa Hospital Research Institute
Emily E. F. Brown: Ottawa Hospital Research Institute
Natalie Crawford: Ottawa Hospital Research Institute
Almohanad Alkayyal: Ottawa Hospital Research Institute
Abera Surendran: Ottawa Hospital Research Institute
Ragunath Singaravelu: Ottawa Hospital Research Institute
Dominic G. Roy: Ottawa Hospital Research Institute
Gemma Migneco: University of Leeds
Benjamin McSweeney: Ottawa Hospital Research Institute
Mary Lynn Cottee: Ottawa Hospital Research Institute
Egon J. Jacobus: Ottawa Hospital Research Institute
Brian A. Keller: Ottawa Hospital Research Institute
Takafumi N. Yamaguchi: University of California, Los Angeles
Paul C. Boutros: University of California, Los Angeles
Michele Geoffrion: University of Ottawa Heart Institute
Katey J. Rayner: University of Ottawa
Avijit Chatterjee: The Ottawa Hospital, Division of Gastroenterology
Rebecca C. Auer: Ottawa Hospital Research Institute
Jean-Simon Diallo: Ottawa Hospital Research Institute
Derrick Gibbings: University of Ottawa
Benjamin R. tenOever: Department of Microbiology, Icahn School of Medicine at Mount Sinai
Alan Melcher: Institute of Cancer Research
John C. Bell: Ottawa Hospital Research Institute
Carolina S. Ilkow: Ottawa Hospital Research Institute

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29526-8

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