Regenerative potential of prostate luminal cells revealed by single-cell analysis

Abstract

Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cell RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1+ and Psca+) and a large population of differentiated cells (Nkx3.1+, Pbsn+). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.

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.…”

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

“…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.…”

“…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.…”