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

Author

Listed:
  • Marie-Eve Wedge

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Victoria A. Jennings

    (Ottawa Hospital Research Institute
    Institute of Cancer Research
    University of Leeds)

  • Mathieu J. F. Crupi

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Joanna Poutou

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Taylor Jamieson

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Adrian Pelin

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • 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
    University of Ottawa)

  • Nouf Alluqmani

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Hayley E. McKay

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Larissa Pikor

    (Ottawa Hospital Research Institute)

  • Sarwat Tahsin Khan

    (Ottawa Hospital Research Institute)

  • Taha Azad

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Reza Rezaei

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Bradley Austin

    (Ottawa Hospital Research Institute)

  • Xiaohong He

    (Ottawa Hospital Research Institute)

  • David Mansfield

    (Institute of Cancer Research)

  • Elaine Rose

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Emily E. F. Brown

    (Ottawa Hospital Research Institute)

  • Natalie Crawford

    (Ottawa Hospital Research Institute)

  • Almohanad Alkayyal

    (Ottawa Hospital Research Institute
    University of Tabuk)

  • Abera Surendran

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Ragunath Singaravelu

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Dominic G. Roy

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • 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
    University of Oxford)

  • Brian A. Keller

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • Takafumi N. Yamaguchi

    (University of California, Los Angeles)

  • Paul C. Boutros

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Michele Geoffrion

    (University of Ottawa Heart Institute)

  • Katey J. Rayner

    (University of Ottawa
    University of Ottawa Heart Institute)

  • Avijit Chatterjee

    (The Ottawa Hospital, Division of Gastroenterology)

  • Rebecca C. Auer

    (Ottawa Hospital Research Institute
    University of Ottawa
    University of Ottawa)

  • Jean-Simon Diallo

    (Ottawa Hospital Research Institute
    University of Ottawa)

  • 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
    University of Ottawa)

  • Carolina S. Ilkow

    (Ottawa Hospital Research Institute
    University of Ottawa)

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.

Suggested Citation

  • 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 B, 2022. "Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29526-8
    DOI: 10.1038/s41467-022-29526-8
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    References listed on IDEAS

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    1. Aldo Scarpa & David K. Chang & Katia Nones & Vincenzo Corbo & Ann-Marie Patch & Peter Bailey & Rita T. Lawlor & Amber L. Johns & David K. Miller & Andrea Mafficini & Borislav Rusev & Maria Scardoni & , 2017. "Whole-genome landscape of pancreatic neuroendocrine tumours," Nature, Nature, vol. 543(7643), pages 65-71, March.
    2. Rozanne Arulanandam & Cory Batenchuk & Oliver Varette & Chadi Zakaria & Vanessa Garcia & Nicole E. Forbes & Colin Davis & Ramya Krishnan & Raunak Karmacharya & Julie Cox & Anisha Sinha & Andrew Babawy, 2015. "Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
    3. Peter Bailey & David K. Chang & Katia Nones & Amber L. Johns & Ann-Marie Patch & Marie-Claude Gingras & David K. Miller & Angelika N. Christ & Tim J. C. Bruxner & Michael C. Quinn & Craig Nourse & L. , 2016. "Genomic analyses identify molecular subtypes of pancreatic cancer," Nature, Nature, vol. 531(7592), pages 47-52, March.
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