Chai Shoujie, Ruiz-Velasco Carmen, Naghdloo Amin, Pore Milind, Singh Mohan, Matsumoto Nicholas, Kolatkar Anand, Xu Liya, Shishido Stephanie, Aparicio Ana, Zurita Amado J, Hicks James, Kuhn Peter
Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA.
Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
NPJ Precis Oncol. 2022 Jun 21;6(1):41. doi: 10.1038/s41698-022-00289-1.
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). 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.
关于肿瘤转移过程中液体微环境不同区室中循环肿瘤细胞（CTC）生物学的复杂性和可塑性，人们了解甚少。在此，我们运用高清单细胞分析3.0（HDSCA3.0），整合表型组学、基因组学和靶向蛋白质组学，对一名转移性前列腺癌患者疾病快速进展后配对的外周血（PB）和骨髓抽吸物（BMA）中的CTC表型和基因型异质性进行表征。独特的是，我们鉴定出一组基因克隆性CTC，其获得了间充质样状态，并且其存在与克隆谱系中出现的一个亚克隆显著相关。在BMA中观察到的CTC丰度和表型多样性高于PB，并且在两个区室之间还鉴定出基因组改变的差异，表明存在空间异质性。单细胞拷贝数分析进一步检测到CTC簇（也称为微栓子或聚集体）内的克隆异质性以及靶向蛋白质组学检测到的表型变异。总体而言，这些结果在一例侵袭性前列腺癌病例的克隆谱系中鉴定出上皮和间充质CTC，并且还展示了一种单细胞多组学方法，用于解析转移性前列腺癌多介质液体活检中CTC表型和基因型的异质性及关联性。
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