Remaining Prostate Luminal Cells Regenerate after Androgen Deprivation

Loss of luminal cells underlies the dramatic reduction in size of the prostate resulting from androgen-deprivation therapy, a mainstay of prostate cancer treatment. Because mouse experiments have shown that testosterone treatment following androgen deprivation can lead to prostate regeneration, possibly from stem cells, Karthaus, Hofree, and colleagues sought to characterize the cells present in the prostate before and during castration and regeneration. Single-cell RNA-sequencing analyses of intact mouse prostates revealed the presence of many cell types, including three types of luminal cells (dubbed L1, L2, and L3) that expressed the established luminal markers Cd24a, Krt8, and Krt18. L1, L2, and L3 cells represented 96%, 3%, and 1% of all luminal cells profiled, respectively. L1 cells expressed androgen receptor–target genes, such as Nkx3.1 and Pbsn; L2 cells expressed genes associated with stemlike properties, such as Sca1 (also known as Ly6a), Tacstd2 (also known as Trop2), and Psca; and L3 cells expressed the transcription-factor gene Foxi1. Experiments in organoids and mice showed that, following castration, L1 and L2 cells contributed equally to prostate regeneration triggered by androgen supplementation. The regeneration potential of these luminal cells was dependent on growth factors such as NRG2 and RSPO3 secreted by prostate mesenchymal cells, and the induction of the genes encoding these growth factors was mediated by androgen receptor. Findings from experiments using patient prostate tissues matched those from the mouse experiments, with androgen deprivation conferring regenerative potential to L1- and L2-like human prostate luminal cells. This study establishes that the vast majority of luminal cells that survive androgen deprivation, rather than a small population of existing stem cells, can contribute to prostate regeneration by acquiring stemlike features. Of note, understanding the mechanism by which this process occurs could be useful in determining how to prevent malignant prostate cells from regenerating following androgen-deprivation therapy.

Karthaus WR, Hofree M, Choi D, Linton EL, Turkekul M, Bejnood A, et al. Regenerative potential of prostate luminal cells revealed by single-cell analysis. Science 2020;368:497–505.

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