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Non-Darwinian dynamics in therapy-induced cancer drug resistance

Author

Listed:
  • Angela Oliveira Pisco

    (Institute for Systems Biology
    Faculty of Life Sciences, University of Manchester)

  • Amy Brock

    (Wyss Institute for Biologically Inspired Engineering at Harvard University
    Present address: Department of Biomedical Engineering, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA)

  • Joseph Zhou

    (Institute for Systems Biology
    Institute for Biocomplexity and Informatics, University of Calgary)

  • Andreas Moor

    (Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research)

  • Mitra Mojtahedi

    (Institute for Systems Biology
    Institute for Biocomplexity and Informatics, University of Calgary)

  • Dean Jackson

    (Faculty of Life Sciences, University of Manchester)

  • Sui Huang

    (Institute for Systems Biology
    Institute for Biocomplexity and Informatics, University of Calgary)

Abstract

The development of drug resistance, the prime cause of failure in cancer therapy, is commonly explained by the selection of resistant mutant cancer cells. However, dynamic non-genetic heterogeneity of clonal cell populations continuously produces metastable phenotypic variants (persisters), some of which represent stem-like states that confer resistance. Even without genetic mutations, Darwinian selection can expand these resistant variants, which would explain the invariably rapid emergence of stem-like resistant cells. Here, by using quantitative measurements and modelling, we show that appearance of multidrug resistance in HL60 leukemic cells following treatment with vincristine is not explained by Darwinian selection but by Lamarckian induction. Single-cell longitudinal monitoring confirms the induction of multidrug resistance in individual cells. Associated transcriptome changes indicate a lasting stress response consistent with a drug-induced switch between high-dimensional cancer attractors. Resistance induction correlates with Wnt pathway upregulation and is suppressed by β-catenin knockdown, revealing a new opportunity for early therapeutic intervention against the development of drug resistance.

Suggested Citation

  • Angela Oliveira Pisco & Amy Brock & Joseph Zhou & Andreas Moor & Mitra Mojtahedi & Dean Jackson & Sui Huang, 2013. "Non-Darwinian dynamics in therapy-induced cancer drug resistance," Nature Communications, Nature, vol. 4(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3467
    DOI: 10.1038/ncomms3467
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    Cited by:

    1. Teemu Kuosmanen & Johannes Cairns & Robert Noble & Niko Beerenwinkel & Tommi Mononen & Ville Mustonen, 2021. "Drug-induced resistance evolution necessitates less aggressive treatment," PLOS Computational Biology, Public Library of Science, vol. 17(9), pages 1-22, September.
    2. Yelyzaveta Shlyakhtina & Bianca Bloechl & Maximiliano M. Portal, 2023. "BdLT-Seq as a barcode decay-based method to unravel lineage-linked transcriptome plasticity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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