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

Alex Hiroto, Won Kyung Kim, Ariana Pineda, Yongfeng He, Dong-Hoon Lee, Vien Le, Adam W. Olson, Joseph Aldahl, Christian H. Nenninger, Alyssa J. Buckley, Guang-Qian Xiao, Joseph Geradts and Zijie Sun ()
Additional contact information
Alex Hiroto: Cancer Center and Beckman Research Institute, City of Hope
Won Kyung Kim: Cancer Center and Beckman Research Institute, City of Hope
Ariana Pineda: Cancer Center and Beckman Research Institute, City of Hope
Yongfeng He: Cancer Center and Beckman Research Institute, City of Hope
Dong-Hoon Lee: Cancer Center and Beckman Research Institute, City of Hope
Vien Le: Cancer Center and Beckman Research Institute, City of Hope
Adam W. Olson: Cancer Center and Beckman Research Institute, City of Hope
Joseph Aldahl: Cancer Center and Beckman Research Institute, City of Hope
Christian H. Nenninger: Cancer Center and Beckman Research Institute, City of Hope
Alyssa J. Buckley: Cancer Center and Beckman Research Institute, City of Hope
Guang-Qian Xiao: University of Southern California
Joseph Geradts: East Carolina University
Zijie Sun: Cancer Center and Beckman Research Institute, City of Hope

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34282-w

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