Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis
Alex Hiroto, Won Kyung Kim, Ariana Pineda, Yongfeng He, Donghoon Lee, Vien Le, Adam W. Olson, Joseph Aldahl, Christian H. Nenninger, Alyssa J. Buckley, Guang‐Qian Xiao, Joseph Geradts, Zijie Sun
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.