Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product

Avanish Mishra, Shih-Bo Huang, Taronish Dubash, Risa Burr, Jon F. Edd, Ben S. Wittner, Quinn E. Cunneely, Victor R. Putaturo, Akansha Deshpande, Ezgi Antmen, Kaustav A. Gopinathan, Keisuke Otani, Yoshiyuki Miyazawa, Ji Eun Kwak, Sara Y. Guay, Justin Kelly, John Walsh, Linda T. Nieman, Isabella Galler, PuiYee Chan, Michael S. Lawrence, Ryan J. Sullivan, Aditya Bardia, Douglas S. Micalizzi, Lecia V. Sequist, Richard J. Lee, Joseph W. Franses, David T. Ting, Patricia A. R. Brunker, Shyamala Maheswaran, David T. Miyamoto (), Daniel A. Haber () and Mehmet Toner ()
Additional contact information
Avanish Mishra: Massachusetts General Hospital and Harvard Medical School
Shih-Bo Huang: Massachusetts General Hospital Cancer Center and Harvard Medical School
Taronish Dubash: Massachusetts General Hospital Cancer Center and Harvard Medical School
Risa Burr: Massachusetts General Hospital Cancer Center and Harvard Medical School
Jon F. Edd: Massachusetts General Hospital and Harvard Medical School
Ben S. Wittner: Massachusetts General Hospital Cancer Center and Harvard Medical School
Quinn E. Cunneely: Massachusetts General Hospital and Harvard Medical School
Victor R. Putaturo: Massachusetts General Hospital and Harvard Medical School
Akansha Deshpande: Massachusetts General Hospital and Harvard Medical School
Ezgi Antmen: Massachusetts General Hospital and Harvard Medical School
Kaustav A. Gopinathan: Massachusetts General Hospital and Harvard Medical School
Keisuke Otani: Massachusetts General Hospital Cancer Center and Harvard Medical School
Yoshiyuki Miyazawa: Massachusetts General Hospital Cancer Center and Harvard Medical School
Ji Eun Kwak: Massachusetts General Hospital Cancer Center and Harvard Medical School
Sara Y. Guay: Massachusetts General Hospital Cancer Center and Harvard Medical School
Justin Kelly: Massachusetts General Hospital Cancer Center and Harvard Medical School
John Walsh: Massachusetts General Hospital and Harvard Medical School
Linda T. Nieman: Massachusetts General Hospital Cancer Center and Harvard Medical School
Isabella Galler: Massachusetts General Hospital Cancer Center and Harvard Medical School
PuiYee Chan: Massachusetts General Hospital Cancer Center and Harvard Medical School
Michael S. Lawrence: Massachusetts General Hospital Cancer Center and Harvard Medical School
Ryan J. Sullivan: Massachusetts General Hospital Cancer Center and Harvard Medical School
Aditya Bardia: Massachusetts General Hospital Cancer Center and Harvard Medical School
Douglas S. Micalizzi: Massachusetts General Hospital Cancer Center and Harvard Medical School
Lecia V. Sequist: Massachusetts General Hospital Cancer Center and Harvard Medical School
Richard J. Lee: Massachusetts General Hospital Cancer Center and Harvard Medical School
Joseph W. Franses: Massachusetts General Hospital Cancer Center and Harvard Medical School
David T. Ting: Massachusetts General Hospital Cancer Center and Harvard Medical School
Patricia A. R. Brunker: Massachusetts General Hospital and Harvard Medical School
Shyamala Maheswaran: Massachusetts General Hospital Cancer Center and Harvard Medical School
David T. Miyamoto: Massachusetts General Hospital Cancer Center and Harvard Medical School
Daniel A. Haber: Massachusetts General Hospital Cancer Center and Harvard Medical School
Mehmet Toner: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from seven patients with metastatic cancer. High CTC yields (mean 10,057 CTCs per patient; range 100 to 58,125) reveal considerable intra-patient heterogeneity. CTC size varies within patients, with 67% overlapping in diameter with WBCs. Paired single-cell DNA and RNA sequencing identifies subclonal patterns of aneuploidy and distinct signaling pathways within CTCs. In prostate cancers, a subpopulation of small aneuploid cells lacking epithelial markers is enriched for neuroendocrine signatures. Pooling of CNV-confirmed CTCs enables whole exome sequencing with high mutant allele fractions. High-throughput CTC enrichment thus enables cell-based liquid biopsy for comprehensive monitoring of cancer.

Date: 2025
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DOI: 10.1038/s41467-024-55140-x

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