A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors

Abstract

Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally-enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.

RUNX1 marks a luminal castration resistant lineage established at the onset of prostate development

“…We demonstrate that these RUNX1 + PLCs exhibit a greater organoid forming potential compared to the remaining luminal fraction, consistent with previous reports isolating similar proximal populations using different markers such as SCA-1, TROP2 or CD26 (Crowley et al, 2020;Goldstein et al, 2008;Guo et al, 2020;Karthaus et al, 2020;Kwon et al, 2016).…”

“…Here, we identified a subset of RUNX1 + luminal cells located in the proximal region of the developing and adult prostate, referred to as RUNX1 + PLCs, and corresponding to the Lum-D cluster identified in our adult scRNA-seq dataset. Of note, this subset appears to be the equivalent of the 'L2' (Karthaus et al, 2020) or 'LumP' (Crowley et al, 2020), or 'Lum-C' (Guo et al, 2020) clusters identified in recent studies. In light of the extensive contribution of RUNX transcription factors to developmental processes (Mevel et al, 2019), our study suggests that Runx1, but also Runx2, may be involved in the development and maintenance of specific subpopulations of the prostate epithelium.…”

“…In particular, our adult scRNA-seq dataset highlighted an extensive degree of cellular heterogeneity, in particular within the luminal epithelia. Several studies recently made similar observations either focusing on the AP (Karthaus et al, 2020), the intact prostate (Crowley et al, 2020;Joseph et al, 2020), or both the intact and castrated prostates (Guo et al, 2020). Integration of these multiple datasets will provide a more global view of the transcriptional landscape of the prostate epithelium.…”

Novel insights in cell cycle dysregulation during prostate cancer progression

“…Simultaneously, others performed singlecell transcriptomics analyses on mouse prostate tissues, and some also validated their findings in benign human prostate tissues that were obtained from adult men (Crowley et al 2020, Guo et al 2020, Karthaus et al 2020. Collectively, these efforts have confirmed the presence of previously unrecognized and functionally diverse prostate epithelial cell populations, which an initial comparative analysis of the transcriptome data sets from these distinct studies has started to reconcile (Crowley et al 2020). The incorporation of mouse models verified the AR-dependence and the regenerative potential of these cell populations in organoid, tissue recombination and in vivo studies (Crowley et al 2020, Karthaus et al 2020, which uncovered that prostate regeneration can be driven by nearly all luminal cells that persist in the prostate after castration, not just rare stem cell populations.…”

“…A pioneering study performed single-cell RNA-seq analyses on benign prostate tissues of healthy young men and uncovered five epithelial cell types, which includedin addition to basal, luminal and NE cell types -also two novel epithelial cell types that are enriched in the prostate urethra and proximal prostatic ducts (Henry et al 2018). Simultaneously, others performed singlecell transcriptomics analyses on mouse prostate tissues, and some also validated their findings in benign human prostate tissues that were obtained from adult men (Crowley et al 2020, Guo et al 2020, Karthaus et al 2020. Collectively, these efforts have confirmed the presence of previously unrecognized and functionally diverse prostate epithelial cell populations, which an initial comparative analysis of the transcriptome data sets from these distinct studies has started to reconcile (Crowley et al 2020).…”