Department of Cancer Biology, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA.
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Nat Commun. 2022 Nov 2;13(1):6552. 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.
雄激素受体（AR）信号通路对于前列腺肿瘤的发生至关重要。尽管人们已经做出了巨大的努力来直接靶向表达 AR 的肿瘤细胞，但这些疗法在大多数前列腺癌患者中都失败了。在这里，我们通过体内实验和小鼠模型证明，间质 Sonic-hedgehog Gli1 谱系细胞中 AR 的缺失会减少前列腺上皮的癌变和肿瘤发展。单细胞 RNA 测序和其他分析表明，通过减弱 AR 对 Sp1 调节转录的抑制，AR 缺失的基质中胰岛素样生长因子（IGF）结合蛋白 3 的表达会显著增加，这进一步抑制了邻近基底上皮细胞中 IGF1 诱导的 Wnt/β-catenin 激活，并抑制其致癌生长和肿瘤发展。来自基质 AR 缺失小鼠的上皮类器官可以恢复 IGF1 诱导的致癌生长。人前列腺肿瘤基底细胞特征的缺失揭示了基质 AR 缺失小鼠的基底细胞中存在这种情况。这些数据表明了前列腺肿瘤发生的一种独特机制，并暗示了针对前列腺癌的基质和上皮 AR 信号的联合靶向治疗。
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