Journal Article

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

Chia, Shumei, Periyasamy, Giridharan, Sharma, Ankur, Kwang, Xue Lin, Gupta, Ruta, Chong, Fui Teen, Thangavelu, Matan Thangavelu, Wong, Angeline Mei Lin, Leong, Hui Sun, Cao, Elaine Yiqun, Zhang, Xiaoqian, Hakimullah, Muhammad, DasGupta, Ramanuj, Iyer, N. Gopalakrishna, Ramakrishnan, Neeraja, Teo, Hui Min Vivian, Kumar, Vibhor, Clark, Jonathan R.

2018

Overview

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. Drug resistance is one of the major causes of cancer-related deaths. Here, the authors using single cell RNA-seq of oral squamous cell carcinoma patient samples pre- and post-cisplatin treatment show that phenotypically homogenous cell populations display cell state plasticity, with poised chromatin marks at mesenchymal genes in epithelial cells, and that the loss of stem factor Sox2 but gain of Sox9 expression (with de novo gain of H3K27ac sites) is associated with drug-induced adaptation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/15 / 38/39 / 38/47 / 38/89 / 45/100 / 45/91 / 631/67/2329 / 631/67/70 / Adaptation / Animals / Antineoplastic Agents - pharmacology / Cancer / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Cell Line, Tumor / Chromatin / Cisplatin / Cisplatin - pharmacology / Divergence / Drug resistance / Drug Resistance, Neoplasm - genetics / Epigenetics / Epithelial cells / Epithelium / Evolution / Fatalities / Gene Expression Profiling - methods / Gene Expression Regulation, Neoplastic / Gene sequencing / Genetic Heterogeneity / Heterogeneity / Humanities and Social Sciences / Humans / Interrogation / Mesenchyme / Mice, Inbred NOD / Mice, Knockout / Mice, SCID / Mouth Neoplasms - drug therapy / Mouth Neoplasms - genetics / Mouth Neoplasms - metabolism / multidisciplinary / Neoplastic Stem Cells - metabolism / Oral cancer / Oral carcinoma / Oral squamous cell carcinoma / Patients / Plastic foam / Plastic properties / Plasticity / Ribonucleic acid / RNA / Science / Sequence Analysis, RNA - methods / Single-Cell Analysis - methods / Sox9 protein / Squamous cell carcinoma / Stem cells / Transcriptomics / Tumor cells / Tumors / Xenograft Model Antitumor Assays