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

PURPOSE: Circulating tumor cells (CTC) with a very-small-nuclear phenotype (vsnCTC) in prostate cancer 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 prostate cancer metastasis and nuclear shape instability. In this study, we investigated the correlation between EMD expression and the vsnCTC phenotype and its clinical impact.

EXPERIMENTAL

DESIGN

We analyzed CTCs from 93 patients with metastatic castration-resistant prostate cancer and categorized them as either vsnCTC+ or vsnCTC- and compared overall survival and progression-free survival. C4-2B, 22Rv1, and DU145 with EMD knockdown were developed and characterized by nuclear size and gene expression by gene set enrichment analysis. Abiraterone- and enzalutamide-resistant C4-2B cells were also characterized by nuclear size and EMD expression.

RESULTS

Patients who were vsnCTC+ had significantly worse overall survival and progression-free survival compared with patients who were vsnCTC-. EMD expression was markedly reduced in CTCs from patients who were vsnCTC+ compared with patients who were vsnCTC-, with a significant positive correlation between EMD expression and CTC nuclear size. EMD knockdown in prostate cancer cells resulted in smaller nuclei, enhanced invasion, and the upregulation of genes associated with lineage plasticity. Additionally, abiraterone- and enzalutamide-resistant C4-2B 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 metastatic castration-resistant prostate cancer 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 prostate cancer.