Urethral luminal epithelia are castration‐insensitive cells of the proximal prostate

Abstract

Background: Castration-insensitive epithelial progenitors capable of regenerating the prostate have been proposed to be concentrated in the proximal region based on facultative assays. Functional characterization of prostate epithelial populations isolated with individual cell surface markers has failed to provide a consensus on the anatomical and transcriptional identity of proximal prostate progenitors.Methods: Here, we use single-cell RNA sequencing to obtain a complete transcriptomic profile of all epithelial cells in the mouse prostate and urethra to objectively identify cellular subtypes. Pan-transcriptomic comparison to human prostate cell types identified a mouse equivalent of human urethral luminal cells, which highly expressed putative prostate progenitor markers. Validation of the urethral luminal cell cluster was performed using immunostaining and flow cytometry.Results: Our data reveal that previously identified facultative progenitors marked by Trop2, Sca-1, KRT4, and PSCA are actually luminal epithelial cells of the urethra that extend into the proximal region of the prostate, and are resistant to castration-induced androgen deprivation. Mouse urethral luminal cells were identified to be the equivalent of previously identified human club and hillock cells that similarly extend into proximal prostate ducts. Benign prostatic hyperplasia (BPH) has long been considered an "embryonic reawakening," but the cellular origin

De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc

“…Antigens associated with the luminal epithelial cells including KRT8 , AR , HOXB13 , KLK3 , and ACPP are expressed at similar levels between the TACSTD2 high and TACSTD2 low luminal cells. In contrast, TACSTD2 high luminal cells express a higher level of PSCA , SOX2 , and KRT7 , which is consistent with the observations from the recent single-cell analyses ( 27 , 29 ).…”

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.…”

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

“…Recently, single-cell transcriptomics performed in the murine AP lobe also revealed a distinct but rare luminal subpopulation anatomically lining the proximal duct and expressing Tacstd2 (Trop2), Psca as well as Ly6a (Sca-1), Krt4 and Cldn10 44 . An independent study suggested that the luminal subpopulation expressing high levels of progenitor markers such as Tacstd2 (Trop2), Psca, Ly6a (Sca-1) and Krt4 corresponds to urethral luminal cells extending into the proximal ducts of the prostate 45 . Since the luminal progenitor population identified in the VP lobe expressed all the aforementioned markers (Supplementary Figure S4A, F), we cannot rule out the possibility that they might be of urethral origin.…”