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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Zi, 2022. "Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34282-w
    DOI: 10.1038/s41467-022-34282-w
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    as
    1. Won Kyung Kim & Adam W. Olson & Jiaqi Mi & Jinhui Wang & Dong-Hoon Lee & Vien Le & Alex Hiroto & Joseph Aldahl & Christian H. Nenninger & Alyssa J. Buckley & Robert Cardiff & Sungyong You & Zijie Sun, 2022. "Aberrant androgen action in prostatic progenitor cells induces oncogenesis and tumor development through IGF1 and Wnt axes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Dingxiao Zhang & Daechan Park & Yi Zhong & Yue Lu & Kiera Rycaj & Shuai Gong & Xin Chen & Xin Liu & Hsueh-Ping Chao & Pamela Whitney & Tammy Calhoun-Davis & Yoko Takata & Jianjun Shen & Vishwanath R. , 2016. "Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
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