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Nat Commun. 2018 Nov 22;9(1):4931. doi: 10.1038/s41467-018-07261-3.

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

Author information

1
Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore. sharmaa@gis.a-star.edu.sg.
2
Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore.
3
Department of Computational Biology, Indraprastha Institute of Information Technology, Okhla Industrial Estate, Phase III, New Delhi, Delhi, 110020, India.
4
National Cancer Centre Singapore, Cancer Therapeutics Research Laboratory, 11 Hospital Drive, 169610, Singapore, Singapore.
5
Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW, 2006, Australia.
6
Chris O'Brien Lifehouse and Sydney Head and Neck Cancer Institute, Sydney, NSW, 2050, Australia.
7
National Cancer Centre Singapore, Cancer Therapeutics Research Laboratory, 11 Hospital Drive, 169610, Singapore, Singapore. gopaliyer@nccs.com.sg.
8
Genome Institute of Singapore, Cancer Therapeutics & Stratified Oncology 5, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore. dasguptar@gis.a-star.edu.sg.

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.

PMID:
30467425
PMCID:
PMC6250721
DOI:
10.1038/s41467-018-07261-3
[Indexed for MEDLINE]
Free PMC Article

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