TY - JOUR
T1 - Identification of epithelial and mesenchymal circulating tumor cells in clonal lineage of an aggressive prostate cancer case
AU - Chai, Shoujie
AU - Ruiz-Velasco, Carmen
AU - Naghdloo, Amin
AU - Pore, Milind
AU - Singh, Mohan
AU - Matsumoto, Nicholas
AU - Kolatkar, Anand
AU - Xu, Liya
AU - Shishido, Stephanie
AU - Aparicio, Ana
AU - Zurita, Amado J.
AU - Hicks, James
AU - Kuhn, Peter
N1 - Funding Information:
The authors would like to thank the patient who participated in this study, Dr. Jeremy Mason, Dr. Rishvanth Kaliappan, Dr. Chen-Ching Peng, Mike Schmidt, Lisa Welter, Nikki Higa, Libere Ndacayisaba, Sonia Maryam Setayesh, Ryan Storgard, Aidan Plant, and Amanda Hmelar for critical reviewing, comments, initial data analysis, or discussions, Dr. Paul Corn for the registration and supervision of “Cabazitaxel With or Without Carboplatin” trial, Kai-Han Tu for sequencing library preparation, Rafael Nevarez for sequencing data generation and raw data collection, Paul Lanctot for the implementation of IMC analytical pipeline, the Technical team for processing samples, Elvia Nunez and Allison Welsh for project/financial management, and BioRender.com with which we created the Fig. . This work is supported fully or partially by the Prostate Cancer Foundation Award 17CHAL01 (A.A., P.K., J.H., S.C.), Breast Cancer Research Foundation Award BCRF-20-089 (J.H., P.K.), NCI’s USC Norris Comprehensive Cancer Center (CORE) Support 5P30CA014089-40 (P.K.), David and Janet Polak Foundation Fellowship in Convergent Science (S.C.), Kalayil & Leela Chacko M.D. Fellowship (S.C.), Vicky Joseph Research Fund, Vassiliadis Research Fund, and Susan Pekarovics.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41698-022-00289-1
DO - 10.1038/s41698-022-00289-1
M3 - Article
C2 - 35729213
AN - SCOPUS:85132804216
SN - 2397-768X
VL - 6
JO - npj Precision Oncology
JF - npj Precision Oncology
IS - 1
M1 - 41
ER -