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Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration

ABSTRACT: Identification of defined cell populations with stem/progenitor properties is key for our understanding of prostate development and tumorigenesis. Prior studies have provided strong evidence of the existence of prostate luminal progenitors, but their identity and functional properties remains unknown. Using an unbiased novel bigenic mouse model to specifically earmark, prospectively isolate, and functionally characterize the quiescent stem-like cells, we identify a label-retaining cell (LRC) population in the mouse prostate luminal cell layer as candidate luminal progenitors. Through comprehensive molecular and biological characterizations, we show that these luminal LRCs exhibit relative dormancy with significant enrichment in the mouse proximal prostate, display bipotent potential in both in vitro organoid formation and the in vivo prostate regeneration assay, express a stem/progenitor gene signature with resemblance to aggressive prostate cancer. Importantly, these luminal LRCs maintain a lower level of Ar expression, are androgen-independent, and resist castration in vivo. Furthermore, analysis of phenotypic markers by immunefluorescent staining reveals heterogeneity within luminal progenitor cell pool. Collectively, our studies establish luminal LRCs as progenitors that may serve as a cellular origin for castration resistant prostate cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE98760 | GEO | 2017/12/21

SECONDARY ACCESSION(S): PRJNA386156

REPOSITORIES: GEO

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Project description:Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen-deprivation remain poorly described despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild type mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin?/Sca-1+/CD49fmed). Here we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumorigenesis. In intact mice, we show that LSCmed prevalence remains low (5-10% of epithelial cells) when prostatic androgen receptor signaling unaltered (malignant Hi-Myc mice) but significantly increases in models exhibiting reduced prostatic androgen receptor signaling, rising up to 30% in premalignant tumors (Pb-PRL mice) and to >80% in castration-resistant prostate tumors driven by Pten loss (Ptenpc-/- mice). LSCmed tolerance to androgen deprivation was demonstrated by their persistence (Ptenpc-/-) or further enrichment (Pb-PRL) 2-3 weeks after castration as evidenced by FACS analysis. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signaling is markedly decreased, which explains why LSCmed tolerate androgen-deprivation. This also enlightens why Ptenpc-/- tumors are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, BrdU staining revealed massive proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. In all, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

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Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration

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