A non-genetic, cell cycle dependent mechanism of platinum resistance in lung adenocarcinoma

  1. Alvaro Gonzalez Rajal  Is a corresponding author
  2. Kamila A Marzec
  3. Rachael A McCloy
  4. Max Nobis
  5. Venessa Chin
  6. Jordan F Hastings
  7. Kaitao Lai
  8. Marina Kennerson
  9. William E Hughes
  10. Vijesh Vaghjiani
  11. Paul Timpson
  12. Jason E Cain
  13. D Neil Watkins
  14. David R Croucher  Is a corresponding author
  15. Andrew Burgess  Is a corresponding author
  1. Garvan Institute of Medical Research, Australia
  2. University of Sydney, Australia
  3. Children's Medical Research Institute, Australia
  4. Hudson Institute of Medical Research, Australia
  5. Research Institute in Oncology and Hematology, Canada

Abstract

We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.

Data availability

Raw RNAseq data has been uploaded to the NCBI Gene Expression Omnibus (GEO) data repository with the accession number GSE161800.

The following data sets were generated

Article and author information

Author details

  1. Alvaro Gonzalez Rajal

    The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
    For correspondence
    a.rajal@garvan.org.au
    Competing interests
    The authors declare that no competing interests exist.
  2. Kamila A Marzec

    ANZAC Research Insitute, University of Sydney, Concord, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Rachael A McCloy

    The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Max Nobis

    Cancer Division, Garvan Institute of Medical Research, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1861-1390
  5. Venessa Chin

    The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Jordan F Hastings

    The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Kaitao Lai

    ANZAC Research Insitute, University of Sydney, Concord, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Marina Kennerson

    ANZAC Research Insitute, University of Sydney, Concord, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. William E Hughes

    Children's Medical Research Institute, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Vijesh Vaghjiani

    Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Paul Timpson

    Cancer Division, Garvan Institute of Medical Research, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Jason E Cain

    Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. D Neil Watkins

    CancerCare Manitoba, Research Institute in Oncology and Hematology, Winnipeg, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. David R Croucher

    The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia
    For correspondence
    d.croucher@garvan.org.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4965-8674
  15. Andrew Burgess

    ANZAC Research Insitute, University of Sydney, Concord, Australia
    For correspondence
    andrew.burgess@sydney.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4536-9226

Funding

National Breast Cancer Foundation (IIRS-18-103)

  • Andrew Burgess

Tour de Cure (RSP-230-2020)

  • Andrew Burgess

Cancer Institute NSW (10/FRL/3-02)

  • Andrew Burgess

Cancer Institute NSW (2013/FRL102)

  • David R Croucher

Cancer Institute NSW (15/REG/1-17)

  • David R Croucher

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were carried out in compliance with the Australian code for the care and use of animals for scientific purposes and in compliance with Garvan Institute of Medical Research/St. Vincent's Hospital Animal Ethics Committee guidelines (ARA_18_17, ARA_16_13).

Reviewing Editor

  1. Maureen E Murphy, The Wistar Institute, United States

Publication history

  1. Received: December 1, 2020
  2. Accepted: May 11, 2021
  3. Accepted Manuscript published: May 13, 2021 (version 1)
  4. Version of Record published: May 31, 2021 (version 2)
  5. Version of Record updated: June 7, 2021 (version 3)

Copyright

© 2021, Gonzalez Rajal et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alvaro Gonzalez Rajal
  2. Kamila A Marzec
  3. Rachael A McCloy
  4. Max Nobis
  5. Venessa Chin
  6. Jordan F Hastings
  7. Kaitao Lai
  8. Marina Kennerson
  9. William E Hughes
  10. Vijesh Vaghjiani
  11. Paul Timpson
  12. Jason E Cain
  13. D Neil Watkins
  14. David R Croucher
  15. Andrew Burgess
(2021)
A non-genetic, cell cycle dependent mechanism of platinum resistance in lung adenocarcinoma
eLife 10:e65234.
https://doi.org/10.7554/eLife.65234

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