Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-018-07261-3
Title: Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy
Authors: Sharma, A
Cao, E.Y
Kumar, V
Zhang, X
Leong, H.S
Wong, A.M.L
Ramakrishnan, N
Hakimullah, M
Teo, H.M.V
Chong, F.T
Chia, S
Thangavelu, M.T
Kwang, X.L
Gupta, R
Clark, J.R
Periyasamy, G
Iyer, N.G 
DasGupta, R
Keywords: 4 (4 chlorophenyl) 2,3,9 trimethyl 6h thieno[3,2 f][1,2,4]triazolo[4,3 a][1,4]diazepine 6 acetic acid tert butyl ester
cisplatin
cytokeratin 18
cytokeratin 8
epithelial cell adhesion molecule
histone H3
RNA
transcription factor Sox2
transcription factor Sox9
uvomorulin
vimentin
antineoplastic agent
cisplatin
adaptation
animal experiment
animal model
Article
cancer chemotherapy
cancer resistance
cell plasticity
cell proliferation
chromatin
controlled study
head and neck squamous cell carcinoma
histone acetylation
human
human cell
mouse
nonhuman
phenotype
primary cell
RNA sequence
single cell analysis
stem cell
transcriptomics
tumor xenograft
animal
cancer stem cell
drug resistance
drug screening
gene expression profiling
gene expression regulation
genetic heterogeneity
genetics
knockout mouse
metabolism
mouth tumor
nonobese diabetic mouse
procedures
SCID mouse
sequence analysis
single cell analysis
squamous cell carcinoma
tumor cell line
Animals
Antineoplastic Agents
Carcinoma, Squamous Cell
Cell Line, Tumor
Cisplatin
Drug Resistance, Neoplasm
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Heterogeneity
Humans
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Mouth Neoplasms
Neoplastic Stem Cells
Sequence Analysis, RNA
Single-Cell Analysis
Xenograft Model Antitumor Assays
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Sharma, A, Cao, E.Y, Kumar, V, Zhang, X, Leong, H.S, Wong, A.M.L, Ramakrishnan, N, Hakimullah, M, Teo, H.M.V, Chong, F.T, Chia, S, Thangavelu, M.T, Kwang, X.L, Gupta, R, Clark, J.R, Periyasamy, G, Iyer, N.G, DasGupta, R (2018). Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy. Nature Communications 9 (1) : 4931. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-018-07261-3
Rights: Attribution 4.0 International
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. © 2018, The Author(s).
Source Title: Nature Communications
URI: https://scholarbank.nus.edu.sg/handle/10635/178380
ISSN: 2041-1723
DOI: 10.1038/s41467-018-07261-3
Rights: Attribution 4.0 International
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