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Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy

Author

Listed:
  • Ankur Sharma

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Elaine Yiqun Cao

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Vibhor Kumar

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5
    Indraprastha Institute of Information Technology)

  • Xiaoqian Zhang

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Hui Sun Leong

    (National Cancer Centre Singapore, Cancer Therapeutics Research Laboratory)

  • Angeline Mei Lin Wong

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Neeraja Ramakrishnan

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Muhammad Hakimullah

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Hui Min Vivian Teo

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Fui Teen Chong

    (National Cancer Centre Singapore, Cancer Therapeutics Research Laboratory)

  • Shumei Chia

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Matan Thangavelu Thangavelu

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • Xue Lin Kwang

    (National Cancer Centre Singapore, Cancer Therapeutics Research Laboratory)

  • Ruta Gupta

    (Royal Prince Alfred Hospital and University of Sydney)

  • Jonathan R. Clark

    (Chris O’Brien Lifehouse and Sydney Head and Neck Cancer Institute)

  • Giridharan Periyasamy

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

  • N. Gopalakrishna Iyer

    (National Cancer Centre Singapore, Cancer Therapeutics Research Laboratory)

  • Ramanuj DasGupta

    (Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5)

Abstract

Chemo-resistance is one of the major causes of cancer-related deaths. Here we used single-cell transcriptomics to investigate divergent modes of chemo-resistance in tumor cells. We observed that higher degree of phenotypic intra-tumor heterogeneity (ITH) favors selection of pre-existing drug-resistant cells, whereas phenotypically homogeneous cells engage covert epigenetic mechanisms to trans-differentiate under drug-selection. This adaptation was driven by selection-induced gain of H3K27ac marks on bivalently poised resistance-associated chromatin, and therefore not expressed in the treatment-naïve setting. Mechanistic interrogation of this phenomenon revealed that drug-induced adaptation was acquired upon the loss of stem factor SOX2, and a concomitant gain of SOX9. Strikingly we observed an enrichment of SOX9 at drug-induced H3K27ac sites, suggesting that tumor evolution could be driven by stem cell-switch-mediated epigenetic plasticity. Importantly, JQ1 mediated inhibition of BRD4 could reverse drug-induced adaptation. These results provide mechanistic insights into the modes of therapy-induced cellular plasticity and underscore the use of epigenetic inhibitors in targeting tumor evolution.

Suggested Citation

  • Ankur Sharma & Elaine Yiqun Cao & Vibhor Kumar & Xiaoqian Zhang & Hui Sun Leong & Angeline Mei Lin Wong & Neeraja Ramakrishnan & Muhammad Hakimullah & Hui Min Vivian Teo & Fui Teen Chong & Shumei Chia, 2018. "Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07261-3
    DOI: 10.1038/s41467-018-07261-3
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    Cited by:

    1. Hong Sheng Quah & Elaine Yiqun Cao & Lisda Suteja & Constance H. Li & Hui Sun Leong & Fui Teen Chong & Shilpi Gupta & Camille Arcinas & John F. Ouyang & Vivian Ang & Teja Celhar & Yunqian Zhao & Hui C, 2023. "Single cell analysis in head and neck cancer reveals potential immune evasion mechanisms during early metastasis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Junyi Chen & Xiaoying Wang & Anjun Ma & Qi-En Wang & Bingqiang Liu & Lang Li & Dong Xu & Qin Ma, 2022. "Deep transfer learning of cancer drug responses by integrating bulk and single-cell RNA-seq data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Suhas V. Vasaikar & Adam K. Savage & Qiuyu Gong & Elliott Swanson & Aarthi Talla & Cara Lord & Alexander T. Heubeck & Julian Reading & Lucas T. Graybuck & Paul Meijer & Troy R. Torgerson & Peter J. Sk, 2023. "A comprehensive platform for analyzing longitudinal multi-omics data," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Daniele Ramazzotti & Fabrizio Angaroni & Davide Maspero & Gianluca Ascolani & Isabella Castiglioni & Rocco Piazza & Marco Antoniotti & Alex Graudenzi, 2022. "Variant calling from scRNA-seq data allows the assessment of cellular identity in patient-derived cell lines," Nature Communications, Nature, vol. 13(1), pages 1-3, December.

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