Circulating tumor cells (CTCs) with a very-small-nuclear phenotype (vsnCTCs) in prostate cancer (PCa) are characterized by nuclei smaller than 8.5 μm. Our previous studies established an association between vsnCTCs and visceral metastasis. Reduction of emerin (EMD), a nuclear envelope protein, contributes to PCa metastasis and nuclear shape instability. Here we investigated the correlation between EMD expression and the vsnCTC phenotype and its clinical impact.
We analyzed CTCs from 93 mCRPC patients and categorized them as either vsnCTC+ or vsnCTC- and compared overall survival (OS) and progression-free survival (PFS). C4-2B, 22Rv1, and DU145 with EMD knockdown were developed and characterized by nuclear size and gene expression by GSEA analysis. Abiraterone- and enzalutamide-resistant (Abi-R/Enza-R) C4-2B cells were also characterized by nuclear size and EMD expression.
vsnCTC+ patients had significantly worse OS and PFS compared to vsnCTC- patients. EMD expression was markedly reduced in CTCs from vsnCTC+ patients compared to vsnCTC- patients, with a significant positive correlation between EMD expression and CTC nuclear size. EMD knockdown in PCa cells resulted in smaller nuclei, enhanced invasion, and the upregulation of genes associated with lineage plasticity. Additionally, C4-2B Abi-R/Enza-R cells had smaller nuclei and lower EMD expression. vsnCTC+ cells also showed enhanced platinum sensitivity.
The presence of vsnCTCs represents a novel hallmark of an aggressive subtype of mCRPC, closely linked to EMD loss and lineage plasticity. These findings highlight the importance of EMD dysregulation in the vsn phenotype, disease progression, and therapeutic resistance in patients with PCa.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2025 Mar 10 [Epub ahead of print]
Le Zhang, Pai-Chi Teng, Karen A Cavassani, Jasmine Wang, Catherine Grasso, Joshua Watson, Zijing Chen, Kai-Han Tu, Brenda Salumbides, Krizia Rohena-Rivera, Lilit Gevorkian, Minhyung Kim, Sungyong You, Dolores Di Vizio, Howard M Sandler, Timothy Daskivich, Neil A Bhowmick, Michael R Freeman, Hsian-Rong Tseng, Jie-Fu Chen, Edwin M Posadas
Cedars-Sinai Medical Center, Los Angeles, CA, United States., Cardinal Tien Hospital, New Taipei, Taiwan., Cedars-Sinai Medical Center, Los Angeles, United States., Cedars-Sinai Medical Center, United States., Cedars-Sinai Medical Center, Los Angeles, California, United States., Cedars-Sinai Medical Center/Boston Children's Hospital, Los Angeles, CA, United States., University of California, Los Angeles, Los Angeles, California, United States., Memorial Sloan Kettering Cancer Center, New York, NY, United States.