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.
Cancer Res; 78(4); 853-64. ©2017 AACR.