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

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 and Zijie Sun ()
Additional contact information
Won Kyung Kim: Cancer Center and Beckman Research Institute, City of Hope
Adam W. Olson: Cancer Center and Beckman Research Institute, City of Hope
Jiaqi Mi: Cancer Center and Beckman Research Institute, City of Hope
Jinhui Wang: 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
Alex Hiroto: 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
Robert Cardiff: University of California at Davis
Sungyong You: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
Zijie Sun: Cancer Center and Beckman Research Institute, City of Hope

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32119-0

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