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, Hui-ming Huang

Research output: Contribution to journalArticle

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Abstract

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 G2–M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle–related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico 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. Significance: 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.

Original languageEnglish (US)
Pages (from-to)853-864
Number of pages12
JournalCancer Research
Volume78
Issue number4
DOIs
StatePublished - Feb 15 2018

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Androgens
Prostatic Neoplasms
RNA
Genes
Neoplasms
Atlases
Androgen Receptors
Gene Expression Profiling
Mitosis
Drug Resistance
ROC Curve
Computer Simulation
Cluster Analysis
Cell Cycle
Up-Regulation
Therapeutics
Clone Cells
Genome
Gene Expression
Recurrence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Single-Cell RNA-seq reveals a subpopulation of prostate cancer cells with enhanced cell-Cycle–Related transcription and attenuated androgen response. / Horning, Aaron M.; Wang, Yao; Lin, Che Kuang; Louie, Anna D.; Jadhav, Rohit R.; Hung, Chia Nung; Wang, Chiou Miin; Lin, Chun Lin; Kirma, Nameer B; Liss, Michael A; Kumar, Addanki P; Sun, Luzhe; Liu, Zhijie; Chao, Wei Ting; Wang, Qianben; Jin, Victor X; Chen, Chun-liang; Huang, Hui-ming.

In: Cancer Research, Vol. 78, No. 4, 15.02.2018, p. 853-864.

Research output: Contribution to journalArticle

Horning, Aaron M. ; Wang, Yao ; Lin, Che Kuang ; Louie, Anna D. ; Jadhav, Rohit R. ; Hung, Chia Nung ; Wang, Chiou Miin ; Lin, Chun Lin ; Kirma, Nameer B ; Liss, Michael A ; Kumar, Addanki P ; Sun, Luzhe ; Liu, Zhijie ; Chao, Wei Ting ; Wang, Qianben ; Jin, Victor X ; Chen, Chun-liang ; Huang, Hui-ming. / Single-Cell RNA-seq reveals a subpopulation of prostate cancer cells with enhanced cell-Cycle–Related transcription and attenuated androgen response. In: Cancer Research. 2018 ; Vol. 78, No. 4. pp. 853-864.
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abstract = "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 G2–M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle–related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico 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. Significance: 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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AU - Wang, Yao

AU - Lin, Che Kuang

AU - Louie, Anna D.

AU - Jadhav, Rohit R.

AU - Hung, Chia Nung

AU - Wang, Chiou Miin

AU - Lin, Chun Lin

AU - Kirma, Nameer B

AU - Liss, Michael A

AU - Kumar, Addanki P

AU - Sun, Luzhe

AU - Liu, Zhijie

AU - Chao, Wei Ting

AU - Wang, Qianben

AU - Jin, Victor X

AU - Chen, Chun-liang

AU - Huang, Hui-ming

PY - 2018/2/15

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N2 - 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 G2–M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle–related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico 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. Significance: 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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