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.

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©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
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First page of Emerin Dysregulation Drives the Very-Small-Nuclear Phenotype and Lineage Plasticity That Associate with a Clinically Aggressive Subtype of Prostate Cancer<alt-title alt-title-type="short">Emerin Drives the vsnCTC Phenotype in Prostate Cancer</alt-title>

Supplementary data

Supplemental Figure 1

Supplemental Figure 1. A general workflow and method of NanoVelcro CTC Enumeration Assay.

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Supplemental Figure 2

Supplemental Figure 2. vsnCTCs are associated with poorer clinical outcomes in advanced prostate cancer.

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Supplemental Figure 3

Supplemental Figure 3. P-spline curve comparing CTC number and hazard ratio for overall survival.

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Supplemental Figure 4

Supplemental Figure 4. Western-blot of EMD in 22Rv1 EMD-knockdown cells by siRNA.

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Supplemental Figure 5

Supplemental Figure 5. Western-blot of EMD in 22Rv1 and C4-2B EMD-knockdown cells by shRNA.

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Supplemental Figure 6

Supplemental Figure 6. Cell Viability of 22Rv1 EMD knockdown cells by shRNA after 5 days treatment of 10 µM abiraterone acetate A), and 5 µM enzalutamide (ENZA) B).

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Supplemental Table 1

Supplemental Table 1. Real-time PCR Oligonucleotide Sequence.

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Supplemental Table 2

Supplemental Table 2. Univariate and multivariable Cox regression analyses.

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Supplemental Table 3

Supplemental Table 3. All subsequent treatments after vsnCTC assessment.

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Supplemental Table 4

Supplemental Table 4. Univariate and multivariable Cox regression analyses for patients with detectable CTCs adjusted for minimum nuclear size.

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