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

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, Matan Thangavelu Thangavelu, Xue Lin Kwang, Ruta Gupta, Jonathan R. Clark, Giridharan Periyasamy, N. Gopalakrishna Iyer () and Ramanuj DasGupta ()
Additional contact information
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
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

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07261-3

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