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

Shoujie Chai; Carmen Ruiz-Velasco; Amin Naghdloo; Milind Pore; Mohan Singh; Nicholas Matsumoto; Anand Kolatkar; Liya Xu; Stephanie Shishido; Ana Aparicio; Amado J Zurita; James Hicks; Peter Kuhn

doi:10.1038/s41698-022-00289-1

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

NPJ Precis Oncol. 2022 Jun 21;6(1):41. doi: 10.1038/s41698-022-00289-1.

Authors

Shoujie Chai^{1

2}, Carmen Ruiz-Velasco¹, Amin Naghdloo¹, Milind Pore¹, Mohan Singh¹, Nicholas Matsumoto¹, Anand Kolatkar¹, Liya Xu¹, Stephanie Shishido¹, Ana Aparicio³, Amado J Zurita³, James Hicks^{4

5}, Peter Kuhn^{6

7}

Affiliations

¹ Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA.
² Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
³ Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁴ Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA. jameshic@usc.edu.
⁵ Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA. jameshic@usc.edu.
⁶ Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA. pkuhn@usc.edu.
⁷ Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA. pkuhn@usc.edu.

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.

Grants and funding

P30 CA016672/CA/NCI NIH HHS/United States