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 de 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; Carolina S Ilkow

doi:10.1038/s41467-022-29526-8

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

Nat Commun. 2022 Apr 7;13(1):1898. doi: 10.1038/s41467-022-29526-8.

Authors

Marie-Eve Wedge^#^{1

2}, Victoria A Jennings^#^{1

3

4}, Mathieu J F Crupi^#^{1

5}, Joanna Poutou^#^{1

5}, Taylor Jamieson^{1

5}, Adrian Pelin^{1

5}, Giuseppe Pugliese¹, Christiano Tanese de Souza¹, Julia Petryk¹, Brian J Laight¹, Meaghan Boileau¹, Zaid Taha^{1

5}, Nouf Alluqmani^{1

5}, Hayley E McKay^{1

5}, Larissa Pikor¹, Sarwat Tahsin Khan¹, Taha Azad^{1

5}, Reza Rezaei^{1

5}, Bradley Austin¹, Xiaohong He¹, David Mansfield³, Elaine Rose^{1

5}, Emily E F Brown¹, Natalie Crawford¹, Almohanad Alkayyal^{1

6}, Abera Surendran^{1

5}, Ragunath Singaravelu^{1

5}, Dominic G Roy^{1

5}, Gemma Migneco⁴, Benjamin McSweeney¹, Mary Lynn Cottee¹, Egon J Jacobus^{1

7}, Brian A Keller^{1

5}, Takafumi N Yamaguchi⁸, Paul C Boutros^{8

9

10

11}, Michele Geoffrion¹², Katey J Rayner^{5

12}, Avijit Chatterjee¹³, Rebecca C Auer^{1

5

14}, Jean-Simon Diallo^{1

5}, Derrick Gibbings², Benjamin R tenOever¹⁵, Alan Melcher³, John C Bell^{1

5}, Carolina S Ilkow^{16

17}

Affiliations

¹ Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
² Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
³ Institute of Cancer Research, London, UK.
⁴ Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
⁵ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
⁶ Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.
⁷ Department of Oncology, University of Oxford, Oxford, UK.
⁸ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.
¹¹ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹² University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
¹³ The Ottawa Hospital, Division of Gastroenterology, Ottawa, Ontario, Canada.
¹⁴ Department of Surgery, University of Ottawa, Ottawa, Ontario, Canada.
¹⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. cilkow@uottawa.ca.
¹⁷ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada. cilkow@uottawa.ca.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Extracellular Vesicles*
Humans
MicroRNAs* / genetics
Neoplasms* / therapy
Oncolytic Virotherapy*
Oncolytic Viruses* / genetics

Substances

MicroRNAs

Abstract

Publication types

MeSH terms

Substances

Grants and funding