Modulation of the canonical Wnt activity by androgen signaling in prostate epithelial basal stem cells

Abstract

Both the canonical Wnt signaling and androgen signaling are important factors regulating prostate organogenesis. How these two pathways crosstalk to regulate prostate stem cell functions remain unclear. Here, we show that while canonical Wnt activity is required for prostate basal stem cell multipotency in vivo, ectopic Wnt activity does not promote basal-to-luminal cell differentiation. We provide evidence that androgen signaling may keep Wnt activity in check. In prostate organoid culture from basal cells, dihydrotestosterone (DHT) antagonizes R-spondin-stimulated organoid growth in a concentration-dependent manner. Molecular analyses of organoids under different treatment conditions showed that androgen signaling downregulated the expressions of a Wnt reporter as well as many Wnt target genes.Pathway analysis and gene set enrichment analysis of organoid RNA-seq data also revealed the canonical Wnt signaling as a key pathway distinguishing organoids treated with or without DHT. Notably, DHT treatment enhanced AR and β-catenin binding in the nuclei of prostate organoids, providing possible mechanistic clues. Our results reveal a critical role of AR signaling in modulating canonical Wnt activity in prostate basal cells to regulate their multipotency.

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

“…The development of 3D organoid cultures for both normal and tumor prostate epithelial cells has been instrumental for rapid functional genetic and preclinical drug screens in vitro, as organoids retain primary tissue heterogeneity, self-renewal capacity, and multi-lineage differentiation [ 170 , 207 , 208 ]. Recently, the effects of Wnt activity on mouse basal stem cell-derived prostate organoids were examined, revealing organoids derived from Apc -deficient mouse prostate basal cells were significantly larger and displayed complex branching relative to wild-type controls, indicating Wnt signaling promotes basal stem cell activities and organoid growth [ 209 ]. Furthermore, DHT treatment reduced Wnt target gene expression, suggesting androgen signaling negatively regulates Wnt signaling in this setting [ 209 ].…”

“…Recently, the effects of Wnt activity on mouse basal stem cell-derived prostate organoids were examined, revealing organoids derived from Apc -deficient mouse prostate basal cells were significantly larger and displayed complex branching relative to wild-type controls, indicating Wnt signaling promotes basal stem cell activities and organoid growth [ 209 ]. Furthermore, DHT treatment reduced Wnt target gene expression, suggesting androgen signaling negatively regulates Wnt signaling in this setting [ 209 ].…”