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Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

Author

Listed:
  • Rozanne Arulanandam

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Cory Batenchuk

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Oliver Varette

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Chadi Zakaria

    (Goodman Cancer Center, McGill University)

  • Vanessa Garcia

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Nicole E. Forbes

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Colin Davis

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Ramya Krishnan

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Raunak Karmacharya

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Julie Cox

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Anisha Sinha

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Andrew Babawy

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Katherine Waite

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Erica Weinstein

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Theresa Falls

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Andrew Chen

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Jeff Hamill

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Naomi De Silva

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • David P. Conrad

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Harold Atkins

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Kenneth Garson

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Carolina Ilkow

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Mads Kærn

    (Ottawa Institute of Systems Biology, University of Ottawa)

  • Barbara Vanderhyden

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Nahum Sonenberg

    (Goodman Cancer Center, McGill University)

  • Tommy Alain

    (Children’s Hospital of Eastern Ontario Research Institute)

  • Fabrice Le Boeuf

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • John C. Bell

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

  • Jean-Simon Diallo

    (Center for Innovative Cancer Research, Ottawa Hospital Research Institute)

Abstract

In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7410
    DOI: 10.1038/ncomms7410
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    Cited by:

    1. Zaid Taha & Mathieu Joseph François Crupi & Nouf Alluqmani & Duncan MacKenzie & Sydney Vallati & Jack Timothy Whelan & Faiha Fareez & Akram Alwithenani & Julia Petryk & Andrew Chen & Marcus Mathew Spi, 2024. "Complementary dual-virus strategy drives synthetic target and cognate T-cell engager expression for endogenous-antigen agnostic immunotherapy," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. 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.
    3. Naziia Kurmasheva & Aida Said & Boaz Wong & Priscilla Kinderman & Xiaoying Han & Anna H. F. Rahimic & Alena Kress & Madalina E. Carter-Timofte & Emilia Holm & Demi Horst & Christoph F. Kollmann & Zhen, 2024. "Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways," Nature Communications, Nature, vol. 15(1), pages 1-28, December.

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