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Identification of epithelial and mesenchymal circulating tumor cells in clonal lineage of an aggressive prostate cancer case.

ABSTRACT: Little is known about the complexity and plasticity of circulating tumor cell (CTC) biology in different compartments of the fluid microenvironment during tumor metastasis. Here we integrated phenomics, genomics, and targeted proteomics to characterize CTC phenotypic and genotypic heterogeneity in paired peripheral blood (PB) and bone marrow aspirate (BMA) from a metastatic prostate cancer patient following the rapid disease progression, using the High-Definition Single Cell Assay 3.0 (HDSCA3.0). Uniquely, we identified a subgroup of genetically clonal CTCs that acquired a mesenchymal-like state and its presence was significantly associated with one subclone that emerged along the clonal lineage. Higher CTC abundance and phenotypic diversity were observed in the BMA than PB and differences in genomic alterations were also identified between the two compartments demonstrating spatial heterogeneity. Single cell copy number profiling further detected clonal heterogeneity within clusters of CTCs (also known as microemboli or aggregates) as well as phenotypic variations by targeted proteomics. Overall, these results identify epithelial and mesenchymal CTCs in the clonal lineage of an aggressive prostate cancer case and also demonstrate a single cell multi-omic approach to deconvolute the heterogeneity and association of CTC phenotype and genotype in multi-medium liquid biopsies of metastatic prostate cancer.

SUBMITTER: Chai S

PROVIDER: S-EPMC9213535 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Identification of epithelial and mesenchymal circulating tumor cells in clonal lineage of an aggressive prostate cancer case.

Chai Shoujie S Ruiz-Velasco Carmen C Naghdloo Amin A Pore Milind M Singh Mohan M Matsumoto Nicholas N Kolatkar Anand A Xu Liya L Shishido Stephanie S Aparicio Ana A Zurita Amado J AJ Hicks James J Kuhn Peter P

NPJ precision oncology 20220621 1

Little is known about the complexity and plasticity of circulating tumor cell (CTC) biology in different compartments of the fluid microenvironment during tumor metastasis. Here we integrated phenomics, genomics, and targeted proteomics to characterize CTC phenotypic and genotypic heterogeneity in paired peripheral blood (PB) and bone marrow aspirate (BMA) from a metastatic prostate cancer patient following the rapid disease progression, using the High-Definition Single Cell Assay 3.0 (HDSCA3.0) ...[more]

PMID: 35729213

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Project description:Simple Summary Circulating tumor cells (CTCs) are important diagnostic and prognostic markers in cancer patients. However, current methods for isolating CTCs primarily focus on epithelial markers, such as EpCAM, leading to the underrepresentation of mesenchymal CTCs. This study proposes a novel method for continuous CTC isolation using magnetic nanoparticles coated with both EpCAM and vimentin antibodies, a mesenchymal marker. Using lateral magnetophoresis, the method demonstrated increased efficiency and reliability in isolating CTCs from patients with prostate (n = 17) and pancreatic (n = 5) cancer. Results indicated that using both EpCAM and vimentin antibodies significantly improved CTC isolation compared to using either marker alone, regardless of cancer stage. Abstract Circulating tumor cells (CTCs) display antigenic heterogeneity between epithelial and mesenchymal phenotypes. However, most current CTC isolation methods rely on EpCAM (epithelial cell adhesion molecule) antibodies. This study introduces a more efficient CTC isolation technique utilizing both EpCAM and vimentin (mesenchymal cell marker) antibodies, alongside a lateral magnetophoretic microseparator. The effectiveness of this approach was assessed by isolating CTCs from prostate (n = 17) and pancreatic (n = 5) cancer patients using EpCAM alone, vimentin alone, and both antibodies together. Prostate cancer patients showed an average of 13.29, 11.13, and 27.95 CTCs/mL isolated using EpCAM alone, vimentin alone, and both antibodies, respectively. For pancreatic cancer patients, the averages were 1.50, 3.44, and 10.82 CTCs/mL with EpCAM alone, vimentin alone, and both antibodies, respectively. Combining antibodies more than doubled CTC isolation compared to single antibodies. Interestingly, EpCAM antibodies were more effective for localized prostate cancer, while vimentin antibodies excelled in metastatic prostate cancer isolation. Moreover, vimentin antibodies outperformed EpCAM antibodies for all pancreatic cancer patients. These results highlight that using both epithelial and mesenchymal antibodies with the lateral magnetophoretic microseparator significantly enhances CTC isolation efficiency, and that antibody choice may vary depending on cancer type and stage.

Project description:BackgroundAlthough circulating tumor cells (CTCs) are considered as a surrogate marker in monitoring disease progression and treatment response in late stage prostate cancer (PCa), its clinical impact in localized PCa remains unclear, indicating the limitation that is simply based on cell count. This perspective observational study aimed to detect the epithelial-to-mesenchymal transition (EMT) subtypes of CTCs in localized PCa and analyze their clinical relevance and application in predicting PCa stages before surgery compared with the Partin table.Patients and methodsBetween August 2017 and April 2019, 80 newly diagnosed localized PCa patients were enrolled in the study. Peripheral blood samples (5 mL) were collected prior to surgery. The CanPatrolTM CTC enrichment technique, a size-based isolation method, was used to detect the EMT CTCs. Clinical relevance of the CTCs was analyzed with Spearman's rank correlation test. Models to predict pathological were built with multivariate logistic regression. Receiver operating characteristic (ROC) curve and area under the curve (AUC) analysis were performed to evaluate the accuracy of the prediction model.ResultsCTCs were detected in 55% of all patients. The biophenotypic CTCs were most valuable and closely correlated with PSA, Gleason score, D'Amico risk classification, and pathological stage in localized PCa. The mesenchymal subtype was rare in this population but associated with seminal vesicle invasion, while the epithelial subtype had limited clinical significance. In addition, the biophenotypic CTCs combined with traditional clinical variables were analyzed by multivariate logistic regression to predict organ-confined disease before surgery, of which the AUC reached 0.818 and was superior to the Partin table 2017 in our cohort.ConclusionThis study highlights the clinical impact of the biophenotypic CTCs in localized PCa, which was most closely related to clinical variables and could help to predict pathology outcomes before surgery.

Dataset Information

Identification of epithelial and mesenchymal circulating tumor cells in clonal lineage of an aggressive prostate cancer case.

Publications

Identification of epithelial and mesenchymal circulating tumor cells in clonal lineage of an aggressive prostate cancer case.

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