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

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. Overall design: Mouse total RNA profiles of a pair of normal mouse prostate label-retaining cells (LRCs) and non-LRCs freshly purified from luminal epithelial cell population by deep RNA-seq.