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Nat. Commun., Feb 09 2024, 15 (1) 1231 | https://doi.org/10.1038/s41467-024-45489-4 Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation

Won Kyung Kim^1,6, Alyssa J. Buckley ^1,6, Dong-Hoon Lee ¹, Alex Hiroto ¹, Christian H. Nenninger ¹, Adam W. Olson ¹, Jinhui Wang ², Zhuo Li ³, Rajeev Vikram ¹, Yao Mawulikplimi Adzavon ¹, Tak-yu Yau ¹, Yigang Bao ¹, Michael Kahn 1, Joseph Geradts⁴, Guang-Qian Xiao ⁵ & Zijie Sun ^1,*

¹Department of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA.
²Integrative Genomics Core, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA.
³Electronic Microscopy Core, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA.
⁴Department of Pathology and Laboratory Medicine, Brody School of Medicine, East Carolina University, Greenville, USA.
⁵Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶These authors contributed equally: Won Kyung Kim, Alyssa J. Buckley.

^*Corresponding author: correspondence to Zijie Sun

Abstract

Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/β-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/β-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets.

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