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

• Published in: Nature communications 2022-11, Vol.13 (1), p.6552-15, Article 6552
• Main Authors: Hiroto, Alex, Kim, Won Kyung, Pineda, Ariana, He, Yongfeng, Lee, Dong-Hoon, Le, Vien, Olson, Adam W., Aldahl, Joseph, Nenninger, Christian H., Buckley, Alyssa J., Xiao, Guang-Qian, Geradts, Joseph, Sun, Zijie
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/51; 14/35; 38/15; 38/77; 38/88; 38/90; 45/88; 631/67/327; 631/67/395; 631/67/589/466; 631/67/70; 64/60; 96/35; 96/95; Androgen receptors; Androgens; Androgens - metabolism; Animal models; Animals; Basal cells; Carcinogenesis - pathology; Cell culture; Epithelial cells; Epithelial Cells - metabolism; Epithelium; Gene sequencing; Growth factors; Humanities and Social Sciences; Humans; Insulin; Insulin-like growth factor I; Insulin-like growth factors; Male; Mice; multidisciplinary; Organoids; Prostate - pathology; Prostate cancer; Prostatic Neoplasms - pathology; Proteins; Receptors; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Science; Science (multidisciplinary); Signal transduction; Signaling; Stromal cells; Stromal Cells - metabolism; Tumor cells; Tumorigenesis; Tumors; Wnt protein; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34282-w

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. Prostate stromal cells can contribute to prostate tumorigenesis. Here the authors show that the loss of androgen receptor signalling in Gli1-lineage stromal cells diminishes prostate epithelial oncogenic transformation and tumor growth in mouse models and this is due to insulin-like growth factor binding protein 3-mediated inhibiting IGF1 and Wnt/β-catenin signalling activation.