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

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

  • Nat Commun. 2022 Nov 2;13(1):6552. doi: 10.1038/s41467-022-34282-w.
Alex Hiroto # 1 Won Kyung Kim # 1 Ariana Pineda 1 Yongfeng He 1 Dong-Hoon Lee 1 Vien Le 1 Adam W Olson 1 Joseph Aldahl 1 Christian H Nenninger 1 Alyssa J Buckley 1 Guang-Qian Xiao 2 Joseph Geradts 3 Zijie Sun 4
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 2 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 3 Department of Pathology and Laboratory Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
  • 4 Department of Cancer Biology, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA. zjsun@coh.org.
  • # Contributed equally.
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.

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