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
  • 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. [email protected].
  • # Contributed equally.
PMID: 35902588 DOI: 10.1038/s41467-022-32119-0
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.

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