1. Academic Validation
  2. Aberrant androgen action in prostatic progenitor cells induces oncogenesis and tumor development through IGF1 and Wnt axes

Aberrant androgen action in prostatic progenitor cells induces oncogenesis and tumor development through IGF1 and Wnt axes

  • Nat Commun. 2022 Jul 28;13(1):4364. doi: 10.1038/s41467-022-32119-0.
Won Kyung Kim  # 1 Adam W Olson  # 1 Jiaqi Mi 1 Jinhui Wang 2 Dong-Hoon Lee 1 Vien Le 1 Alex Hiroto 1 Joseph Aldahl 1 Christian H Nenninger 1 Alyssa J Buckley 1 Robert Cardiff 3 Sungyong You 4 Zijie Sun 5
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 2 Integrative Genomics Core, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • 3 Center for Comparative Medicine, University of California at Davis, Davis, CA, USA.
  • 4 Division of Cancer Biology and Therapeutics, Departments of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 5 Department of Cancer Biology, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA. zjsun@coh.org.
  • # Contributed equally.
Abstract

Androgen/Androgen Receptor (AR) signaling pathways are essential for prostate tumorigenesis. However, the fundamental mechanisms underlying the AR functioning as a tumor promoter in inducing prostatic oncogenesis still remain elusive. Here, we demonstrate that a subpopulation of prostatic Osr1 (odd skipped-related 1)-lineage cells functions as tumor progenitors in prostate tumorigenesis. Single cell transcriptomic analyses reveal that aberrant AR activation in these cells elevates insulin-like growth factor 1 (IGF1) signaling pathways and initiates oncogenic transformation. Elevating IGF1 signaling further cumulates Wnt/β-catenin pathways in transformed cells to promote prostate tumor development. Correlations between altered androgen, IGF1, and Wnt/β-catenin signaling are also identified in human prostate Cancer samples, uncovering a dynamic regulatory loop initiated by the AR through prostate Cancer development. Co-inhibition of androgen and Wnt-signaling pathways significantly represses the growth of AR-positive tumor cells in both ex-vivo and in-vivo, implicating co-targeting therapeutic strategies for these pathways to treat advanced prostate Cancer.

Figures
Products