Emerin Dysregulation Drives the Very-Small-Nuclear Phenotype and Lineage Plasticity that Associates with a Clinically Aggressive Subtype of Prostate Cancer

Background: 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. Methods: 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. Results: 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. Conclusions: 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.