Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle-Related Transcription and Attenuated Androgen Response.
Aaron M Horning, Yao Wang, Che-Kuang Lin, Anna D Louie, Rohit R Jadhav, Chia-Nung Hung, Chiou-Miin Wang, Chun-Lin Lin, Nameer B Kirma, Michael A Liss, Addanki P Kumar, LuZhe Sun, Zhijie Liu, Wei-Ting Chao, Qianben Wang, Victor X Jin, Chun-Liang Chen, Tim H-M Huang
Author Information
Aaron M Horning: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Yao Wang: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Che-Kuang Lin: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Anna D Louie: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Rohit R Jadhav: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Chia-Nung Hung: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Chiou-Miin Wang: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Chun-Lin Lin: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Nameer B Kirma: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Michael A Liss: Department of Urology, University of Texas Health Science Center, San Antonio at San Antonio, Texas.
Addanki P Kumar: Department of Urology, University of Texas Health Science Center, San Antonio at San Antonio, Texas.
LuZhe Sun: Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Zhijie Liu: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Wei-Ting Chao: Department of Life Science, Tunghai University, Taichung, Taiwan.
Qianben Wang: Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
Victor X Jin: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Chun-Liang Chen: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas. chenc4@uthscsa.edu huangt3@uthscsa.edu.
Tim H-M Huang: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas. chenc4@uthscsa.edu huangt3@uthscsa.edu.
Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell-cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G-M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle-related genes (, and ) and decreased dependence upon androgen receptor signaling. analysis of RNA-seq data from The Cancer Genome Atlas further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen deprivation therapies and reveals characteristics of subpopulations resistant to this treatment. Illustrating the challenge in treating cancers with targeted drugs, which by selecting for drug resistance can drive metastatic progression, this study characterized the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, defining the character or minor subpopulations of androgen-independent cells that are poised for clonal selection after androgen-deprivation therapy. .
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