TY - JOUR
T1 - Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing
AU - Lee, Mei Chong Wendy
AU - Lopez-Diaz, Ferno J.
AU - Khan, Shahid Yar
AU - Tariq, Muhammad Akram
AU - Dayn, Yelena
AU - Vaske, Charles Joseph
AU - Radenbaugh, Amie J.
AU - Kim, Hyunsung John
AU - Emerson, Beverly M.
AU - Pourm, Nader
PY - 2014/11/4
Y1 - 2014/11/4
N2 - The acute cellular response to stress generates a subpopulation of reversibly stress-tolerant cells under conditions that are lethal to the majority of the population. Stress tolerance is attributed to heterogeneity of gene expression within the population to ensure survival of a minority. We performed whole transcriptome sequencing analyses of metastatic human breast cancer cells subjected to the chemotherapeutic agent paclitaxel at the single-cell and population levels. Here we show that specific transcriptional programs are enacted within untreated, stressed, and drugtolerant cell groups while generating high heterogeneity between single cells within and between groups. We further demonstrate that drug-tolerant cells contain specific RNA variants residing in genes involved in microtubule organization and stabilization, as well as cell adhesion and cell surface signaling. In addition, the gene expression profile of drug-tolerant cells is similar to that of untreated cells within a few doublings. Thus, single-cell analyses reveal the dynamics of the stress response in terms of cell-specific RNA variants driving heterogeneity, the survival of a minority population through generation of specific RNA variants, and the efficient reconversion of stress-tolerant cells back to normalcy.
AB - The acute cellular response to stress generates a subpopulation of reversibly stress-tolerant cells under conditions that are lethal to the majority of the population. Stress tolerance is attributed to heterogeneity of gene expression within the population to ensure survival of a minority. We performed whole transcriptome sequencing analyses of metastatic human breast cancer cells subjected to the chemotherapeutic agent paclitaxel at the single-cell and population levels. Here we show that specific transcriptional programs are enacted within untreated, stressed, and drugtolerant cell groups while generating high heterogeneity between single cells within and between groups. We further demonstrate that drug-tolerant cells contain specific RNA variants residing in genes involved in microtubule organization and stabilization, as well as cell adhesion and cell surface signaling. In addition, the gene expression profile of drug-tolerant cells is similar to that of untreated cells within a few doublings. Thus, single-cell analyses reveal the dynamics of the stress response in terms of cell-specific RNA variants driving heterogeneity, the survival of a minority population through generation of specific RNA variants, and the efficient reconversion of stress-tolerant cells back to normalcy.
KW - Drug resistance |
KW - Paclitaxel |
KW - RNA-Seq
KW - Single cell |
KW - Tumor heterogeniety |
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U2 - 10.1073/pnas.1404656111
DO - 10.1073/pnas.1404656111
M3 - Article
C2 - 25339441
AN - SCOPUS:84914706587
SN - 0027-8424
VL - 111
SP - E4726-E4735
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 44
ER -