Transferrin Receptor Identifies a Comprehensive Pool of Circulating Tumor Cells with Unique Molecular Features from Metastatic Prostate Cancer Patients
Abstract
Metastatic castration resistant prostate cancer (CRPC) is currently incurable, due to treatment resistance. Elucidation of resistancemechanisms requires frequent tumor sampling to monitor tumor evolution and tailor treatments to the individual. Circulating tumor cells (CTCs) represent anon-invasive, accessible liquid biopsy source of tumor cells, allowing for longitudinal molecular disease profiling. Due to limitations with existing EpCAM-based CTC isolation assays we have identified and clinically tested Transferrin Receptor (TfR) as a novel cell-surface antigen that enables capture of all CTCsacross the EMT gradient from metastatic patients. Mining large datasets (TCGA, SU2C) revealed TfR enrichment in metastatic patients, which significantlycorrelated with advanced state from localized PC to CRPC to the aggressive neuroendocrine NEPC. RNA-seq analysis indicates that TfR+-CTCs possessunique expression profile and are enriched in EMT and tumor progression pathways, as compared to EpCAM+- CTCs. Expression of androgen receptor (AR)splice variants (AR-Vs) is known to drive disease progression. We have developed a highly sensitivedown to single celldigital droplet PCR assay for thequantitation of AR-Vs in patient CTCs. Isolation of TFR+ vs EpCAM+ CTCs from metastatic patients, revealed significant AR-V enrichment in TFR+ CTCs,while AR-FL expression was similar. When we analyzed single CTCs using the same ddPCR assay, we observed even more striking enrichment, with AR-Vs detected in 21% of single TFR+-CTCs vs 0% in EpCAM+-CTCs. These data support our hypothesis that TfR can identify a comprehensive pool of CTCs (not limited to the epithelial-only phenotypes) and provide an accurate representation of metastatic disease burden. To test this, we propose to prospectively collect peripheral blood from CRPC and NEPC patients to 1. Molecularly profile TFR+-CTCs and EpCAM+-CTCs, and matching tumor biopsies, by RNA-Seq to identify the driving oncogenic pathways that correlat
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2020
- Accession Number
- AD1119411
Entities
People
- Paraskevi Giannakakou
Organizations
- Weill Cornell Medicine