A noninvasive prognostic biomarker for metastatic castration-resistant prostate cancer: Very small nuclear circulating tumor cells.

Abstract

179 Background: Circulating tumor cells (CTCs) have arisen as a contemporary biomarker for prostate cancer (PC). A subgroup of PC CTCs, with particularly small nuclei ( < 8.54 μm), were found to be correlated with poor prognosis and the emergence of visceral metastases (VM). This subgroup was named very-small nuclear CTCs (vsnCTCs). The findings led us to explore vsnCTCs as an aggressive biomarker in metastatic castration-resistant PC (mCRPC). We also explored a biological pathway that potentially drives this morphologic phenomenon. Studies showed that the disruption of the linker of nucleoskeleton and cytoskeleton (LINC) complex proteins, such as emerin, results in nuclear envelope instability and drives cancer cells to an amoeboid phenotype with increasing capacity of migration and invasion. We hypothesized that emerin mislocalization is associated with vsnCTC formation and may be a critical step of metastasis. Methods: Using our NanoVelcro CTC assay, we are able to capture and enumerate CTCs from patients' blood and correlate this data with clinical outcomes. We collected samples from 35 mCRPC patients who failed first-line androgen deprivation therapy and started treatment with abiraterone, enzalutamide, or taxane-based chemotherapy. Survival analyses were performed to exam the correlation between vsnCTC counts and patients’ prognosis. Concurrently, emerin staining was performed and the distribution and expression levels were analyzed in selected vsnCTC samples. Results: The presence of one or more vsnCTCs correlated with worse overall survival (P = 0.00013), progression free survival (PSA progression: P = 0.012; radiographic progression: P = 0.0015), and faster time to VM (P = 0.024). We also observed lower emerin content in vsnCTCs compared to WBC, and more prominent emerin mislocalization in vsnCTCs compared to CTCs with larger nuclei. Conclusions: Our study demonstrated the importance of morphologic characterization of CTCs and suggested that vsnCTCs is a putative biomarker for prediction of worse outcome. Additionally, our findings of emerin mislocalization in vsnCTCs suggested a potential biological pathway behind this nuclear morphologic phenomenon.