Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis

Nat Commun. 2022 Nov 2;13(1):6552. doi: 10.1038/s41467-022-34282-w.

Abstract

The androgen receptor (AR)-signaling pathways are essential for prostate tumorigenesis. Although significant effort has been devoted to directly targeting AR-expressing tumor cells, these therapies failed in most prostate cancer patients. Here, we demonstrate that loss of AR in stromal sonic-hedgehog Gli1-lineage cells diminishes prostate epithelial oncogenesis and tumor development using in vivo assays and mouse models. Single-cell RNA sequencing and other analyses identified a robust increase of insulin-like growth factor (IGF) binding protein 3 expression in AR-deficient stroma through attenuation of AR suppression on Sp1-regulated transcription, which further inhibits IGF1-induced Wnt/β-catenin activation in adjacent basal epithelial cells and represses their oncogenic growth and tumor development. Epithelial organoids from stromal AR-deficient mice can regain IGF1-induced oncogenic growth. Loss of human prostate tumor basal cell signatures reveals in basal cells of stromal AR-deficient mice. These data demonstrate a distinct mechanism for prostate tumorigenesis and implicate co-targeting stromal and epithelial AR-signaling for prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androgens / metabolism
  • Animals
  • Carcinogenesis / pathology
  • Epithelial Cells / metabolism
  • Humans
  • Male
  • Mice
  • Prostate* / pathology
  • Prostatic Neoplasms* / pathology
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Stromal Cells / metabolism

Substances

  • Androgens
  • Receptors, Androgen