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Hydro-Seq Improves Circulating Tumor Cells Analysis by High-Throughput scRNA-seq

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May 16, 2019

Hydro-Seq Improves Circulating Tumor Cells Analysis by High-Throughput scRNA-seq

Clean separation of cancer cells from a patient’s blood sample has been an ongoing challenge for the liquid biopsy field. The ability to perform molecular analysis on circulating tumor cells (CTCs) at single-cell resolution offers great promise to advance cancer diagnostics and therapeutics.

A team from the University of Michigan has recently developed Hydro-Seq, which is a scalable hydrodynamic scRNA-seq barcoding technique, for high-throughput CTC analysis. The clean separation of cancer cells from a blood sample would enable comprehensive genetic profiling of the cancer cells and capture the variation among cancer cells within a single patient.

The work is published in Nature Communications in a paper titled “Hydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells.”

Recent development of massively parallel single-cell RNA-sequencing (scRNA-seq) provides a powerful method to resolve the cellular heterogeneity from gene expression and pathway regulation analysis. However, the scarcity of CTCs and the massive contamination of blood cells limit the utility of currently available technologies. Earlier techniques meant a trade-off between a comprehensive genetic profile of a limited subset of cancer cells, or capturing most of the cancer cells and only being able to look for a few genes. As a result, the genetic profiles often neglected important populations of cancer cells.

The key technology of Hydro-Seq is a chip with a system of channels and chambers. It traps cancer cells one at a time by drawing fluid through a drain in each chamber, which gets plugged when a cancer cell arrives. Once the chamber is plugged, cells in the channel pass it by and get sucked into the next chamber. Then, to “wash” the blood cells off the chip, they ran clean fluid backward through the chip and drew it out again, taking nearly all the rest of the contaminating cells along.

With a clean sample of isolated cancer cells, the team captured the transcriptomes with barcoded beads, a method that until now was difficult to use with small cell samples. The team dropped a barcoded bead into each chamber and then closed the chambers before destroying the cell membranes. This released the RNA so that the RNA attached to barcoded genetic code on the bead. The team could then analyze the contents of each cell separately.

Using this method, the team collected and analyzed 666 cancer cells from the blood of 21 breast cancer patients. The genetic analysis confirmed that even within a single patient, the cancer cells often behave very differently. The team has previously shown that cancer metastasis is mediated by cancer cells that have the properties of stem cells. Although cancer stem cells make up only a few percent of a tumor’s cells, they make up a higher proportion of the cancer cells in the bloodstream. In this study, about 30–50% of the cancer cells captured from the blood samples displayed stem-like properties.

Cancer treatment can be a moving target, with cancers changing their gene expression as drugs kill off some cells but not others. the team expects to be using the new device to track the progress of patients in an upcoming drug trial. They said that Hydro-Seq is a very powerful tool to monitor—at the cellular level—what a treatment does to tumors over time. And it allows you not only to select targeted therapies, but to monitor the effects of these therapies in patients by doing this blood test.

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