Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product
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 throu...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55140-x |
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| author | 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 Mehmet Toner |
| author_facet | 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 Mehmet Toner |
| author_sort | Avanish Mishra |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2b7ef863a8e54fc697eca7c075faf194 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2b7ef863a8e54fc697eca7c075faf1942025-01-05T12:37:32ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-55140-xTumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis productAvanish Mishra0Shih-Bo Huang1Taronish Dubash2Risa Burr3Jon F. Edd4Ben S. Wittner5Quinn E. Cunneely6Victor R. Putaturo7Akansha Deshpande8Ezgi Antmen9Kaustav A. Gopinathan10Keisuke Otani11Yoshiyuki Miyazawa12Ji Eun Kwak13Sara Y. Guay14Justin Kelly15John Walsh16Linda T. Nieman17Isabella Galler18PuiYee Chan19Michael S. Lawrence20Ryan J. Sullivan21Aditya Bardia22Douglas S. Micalizzi23Lecia V. Sequist24Richard J. Lee25Joseph W. Franses26David T. Ting27Patricia A. R. Brunker28Shyamala Maheswaran29David T. Miyamoto30Daniel A. Haber31Mehmet Toner32Center for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolDivision of Hematology Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolDivision of Hematology Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolDivision of Hematology Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolDivision of Hematology Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolDivision of Hematology Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolDivision of Hematology Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolDivision of Hematology Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolDepartment of Pathology, Massachusetts General Hospital and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical SchoolCenter for Engineering in Medicine and Surgery, Massachusetts General Hospital and Harvard Medical SchoolAbstract 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.https://doi.org/10.1038/s41467-024-55140-x |
| spellingShingle | 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 Mehmet Toner Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product Nature Communications |
| title | Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product |
| title_full | Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product |
| title_fullStr | Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product |
| title_full_unstemmed | Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product |
| title_short | Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product |
| title_sort | tumor cell based liquid biopsy using high throughput microfluidic enrichment of entire leukapheresis product |
| url | https://doi.org/10.1038/s41467-024-55140-x |
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