A basal stem cell signature identifies aggressive prostate cancer phenotypes

Abstract

Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells. We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACSpurified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organconfined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells.RNA-seq | prostate cancer | stem cell signature | basal cell | neuroendocrine prostate cancer

Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay

“…This finding is consistent with previous observations of slower disease progression and decreased cellular proliferation and tumor invasion in luminal-derived prostate tumors compared with basal-derived tumors in the context of PTEN loss (18). It also coincides with our recent report that aggressive human prostate cancers are enriched for a basal stem cell expression signature (26). In contrast, however, another study found that tumors of luminal origin were more aggressive than tumors of basal origin based on cross-species bioinformatics analyses (3).…”

“…Hi basal cell 1,000 21 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) Intriguingly, human basal-and luminal-derived tumors demonstrate histologically distinct phenotypes when challenged with the same oncogenes, MYC and AKT1. Tumors derived from basal cells are of a higher grade than tumors derived from luminal cells.…”

Sleeping Beautyscreen revealsPpargactivation in metastatic prostate cancer

“…When we looked at the RNA-seq data, we observed that the Pparg INT tumors had an increased basal phenotype compared with the Pparg WT and Pten Null tumors (Fig. S3B), in keeping with a more aggressive phenotype (15). To rule out the effect of the transposon on genes adjacent to Pparg, we could not demonstrate any differentially expressed genes within a 200-kb flanking region around the Pparg locus in those tumors with insertions at this locus (Pparg INT ) [false discover rate (FDR)-corrected Wald test, P < 0.001; P value represents the likelihood (less than 1 in 1,000 chance) of another differentially expressed gene being found flanking a 200-kb region on either side of Pparg].…”

Sample size calculations and normalization methods for RNA-seq data.

“…The corresponding power from the calculated sample size was obtained via a simulation using a two-sided Wald's test statistic in (32).…”

“…Differentially expressed genes (DEGs) or novel transcripts identified by RNA-seq have served as gene signatures for clinical diagnosis, prognosis, and to estimate the efficacy of gene therapy or survival prediction [31][32][33][34][35]. With the rapid growth of clinical trial applications using RNA-seq, sample size estimation methods are critically needed for experimental design.…”