![]() Current liquid biopsy methods for CTC detection usually rely on one particular phenotypic state, traditionally the epithelial state characterized by cytokeratin and/or EpCAM expression 8. This implies that to clearly identify EMT as a state change, the genomic alterations in the original epithelial cell must be evident in the resultant mesenchymal cell. The underlying concept behind EMT is that a malignant epithelial cell changes its phenotypic state to become more mesenchymal-like and motile as a means to increase metastatic potential. Dissecting the genetic mechanism of a phenotypic transition is especially critical in circulating tumor cells (CTCs) with acquired metastatic capability as the key hallmark of cancer 7. Distinguishing phenotypic states of tumor cells with genetically clonal identity and along clonal lineage is important in the investigation of epithelial-mesenchymal transition (EMT) and for understanding the link between genotype and phenotype 5, 6. The mutation, selection, and adaptation of tumor cells along the pathway of disease progression and metastasis results in a spectrum of phenotypic and genomic heterogeneity 1, 2, 3, 4. 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. 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. 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. 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. 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). Little is known about the complexity and plasticity of circulating tumor cell (CTC) biology in different compartments of the fluid microenvironment during tumor metastasis.
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