Microfluidic concentration and separation of circulating tumor cell clusters from large blood volumes

F., Jon; Mishra, Avanish; Dubash, Taronish D.; Herrera, Stefan; Mohammad, Ridhwan; Williams, E. Kendall; Hong, Xin; Mutlu, Baris R.; Walsh, John R.; Carvalho, Fabrício Rodrigues Torres de; Aldikacti, Berent; Nieman, Linda T.; Stott, Shannon L.; Kapur, Ravi; Maheswaran, Shyamala; Haber, Daniel A.; Toner, Mehmet

doi:10.1039/c9lc01122f

Cited by 56 publications

(46 citation statements)

References 41 publications

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“…The second limitation is that the current approach loses very rare CTCs that may travel in association with WBCs ( 49 ). To prevent this loss, we are planning to incorporate a recently developed size-based CTC cluster chip ( 50 ) as the first step in our protocol to isolate CTC clusters and CTC–WBC clusters in a clean buffer.…”

Section: Discussionmentioning

confidence: 99%

Ultrahigh-throughput magnetic sorting of large blood volumes for epitope-agnostic isolation of circulating tumor cells

Mishra

Dubash

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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131

107

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Circulating tumor cell (CTC)-based liquid biopsies provide unique opportunities for cancer diagnostics, treatment selection, and response monitoring, but even with advanced microfluidic technologies for rare cell detection the very low number of CTCs in standard 10-mL peripheral blood samples limits their clinical utility. Clinical leukapheresis can concentrate mononuclear cells from almost the entire blood volume, but such large numbers and concentrations of cells are incompatible with current rare cell enrichment technologies. Here, we describe an ultrahigh-throughput microfluidic chip, LPCTC-iChip, that rapidly sorts through an entire leukapheresis product of over 6 billion nucleated cells, increasing CTC isolation capacity by two orders of magnitude (86% recovery with 105 enrichment). Using soft iron-filled channels to act as magnetic microlenses, we intensify the field gradient within sorting channels. Increasing magnetic fields applied to inertially focused streams of cells effectively deplete massive numbers of magnetically labeled leukocytes within microfluidic channels. The negative depletion of antibody-tagged leukocytes enables isolation of potentially viable CTCs without bias for expression of specific tumor epitopes, making this platform applicable to all solid tumors. Thus, the initial enrichment by routine leukapheresis of mononuclear cells from very large blood volumes, followed by rapid flow, high-gradient magnetic sorting of untagged CTCs, provides a technology for noninvasive isolation of cancer cells in sufficient numbers for multiple clinical and experimental applications.

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Section: Discussionmentioning

confidence: 99%

Ultrahigh-throughput magnetic sorting of large blood volumes for epitope-agnostic isolation of circulating tumor cells

Mishra

Dubash

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

131

107

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“…Then, thermic dissolution of gelatin at 37 • C led to a gentle release of viable CTCs and CTC clusters [61]. Alternatively, microfluidic platforms can specifically isolate CTC clusters, including heterotypic, based on their physical properties (size) without any labeling and preserving their integrity [39,62]. Future developments should aim towards methods that allow phenotypic, molecular, and even functional analyses at once [63].…”

Section: Towards a Better Characterizationmentioning

confidence: 99%

Circulating Tumor Cell Clusters: United We Stand Divided We Fall

Amintas

Bedel

Moreau‐Gaudry

et al. 2020

IJMS

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The presence of circulating tumor cells (CTCs) and CTC clusters, also known as tumor microemboli, in biological fluids has long been described. Intensive research on single CTCs has made a significant contribution in understanding tumor invasion, metastasis tropism, and intra-tumor heterogeneity. Moreover, their being minimally invasive biomarkers has positioned them for diagnosis, prognosis, and recurrence monitoring tools. Initially, CTC clusters were out of focus, but major recent advances in the knowledge of their biogenesis and dissemination reposition them as critical actors in the pathophysiology of cancer, especially metastasis. Increasing evidence suggests that “united” CTCs, organized in clusters, resist better and carry stronger metastatic capacities than “divided” single CTCs. This review gathers recent insight on CTC cluster origin and dissemination. We will focus on their distinct molecular package necessary to resist multiple cell deaths that all circulating cells normally face. We will describe the molecular basis of their increased metastatic potential as compared to single CTCs. We will consider their clinical relevance as prognostic biomarkers. Finally, we will propose future directions for research and clinical applications in this promising topic in cancer.

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“…They also acknowledge that since the chip uses a negative depletion strategy, any CTC-WBC clusters will be lost. As a result, they plan to also incorporate a size-based CTC cluster chip to firstly isolate any CTC clusters prior to enrichment with the LP CTC-iChip [ 140 ].…”

Section: Combined Methodsmentioning

confidence: 99%

A Review of Circulating Tumour Cell Enrichment Technologies

Rushton

Nteliopoulos

Shaw

et al. 2021

Cancers

128

102

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Circulating tumour cells (CTCs) are the precursor cells for the formation of metastatic disease. With a simple blood draw, liquid biopsies enable the non-invasive sampling of CTCs from the blood, which have the potential to provide important insights into cancer detection and monitoring. Since gaining FDA approval in 2004, the CellSearch system has been used to determine the prognosis of patients with metastatic breast, prostate and colorectal cancers. This utilises the cell surface marker Epithelial Cell Adhesion Molecule (EpCAM), to enrich CTCs, and many other technologies have adopted this approach. More recently, the role of mesenchymal-like CTCs in metastasis formation has come to light. It has been suggested that these cells are more aggressive metastatic precursors than their epithelial counterparts; however, mesenchymal CTCs remain undetected by EpCAM-based enrichment methods. This has prompted the development of a variety of ‘label free’ enrichment technologies, which exploit the unique physical properties of CTCs (such as size and deformability) compared to other blood components. Here, we review a wide range of both immunocapture and label free CTC enrichment technologies, summarising the most significant advantages and disadvantages of each. We also highlight the important characteristics that technologies should possess for routine clinical use, since future developments could have important clinical implications, with the potential to direct personalised therapies for patients with cancer.

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Microfluidic concentration and separation of circulating tumor cell clusters from large blood volumes

Abstract: Rare CTC clusters can be purified intact from large blood volumes with a continuous three-stage non-equilibrium inertial separation array (NISA).

Cited by 56 publications

References 41 publications

Ultrahigh-throughput magnetic sorting of large blood volumes for epitope-agnostic isolation of circulating tumor cells

Ultrahigh-throughput magnetic sorting of large blood volumes for epitope-agnostic isolation of circulating tumor cells

Circulating Tumor Cell Clusters: United We Stand Divided We Fall

A Review of Circulating Tumour Cell Enrichment Technologies

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