June 1, 2015

Microchip Captures Clusters of Circulating Tumor Cells

At a Glance

  • Researchers developed a device that can capture rare clusters of tumor cells from the blood of cancer patients.
  • The ability to isolate and study these intact cell clusters could lead to important new insights into how cancer spreads.
Cancer cell cluster. Cancer cell cluster balancing on the tip of a post within the Cluster-Chip.Sarioglu et al., Nature Methods

A tumor is made up of a mass of cells. Rare cells sometimes break away from a tumor and move through the bloodstream. Called circulating tumor cells (CTCs), they can take root in other organs and cause a cancer to spread, or metastasize.

Single CTCs are extremely rare, typically fewer than one in a billion blood cells. Small groups of CTCs, or clusters, are even more elusive. Researchers have known about the existence of CTC clusters for more than 50 years, but their prevalence in blood and their role in metastasis have been poorly understood.

Recent advances in biomedical technologies have enabled researchers to isolate single CTCs for closer study. CTC clusters are occasionally captured along with single CTCs. A research team led by Dr. Mehmet Toner at Massachusetts General Hospital and Harvard Medical School developed a novel microfluidic chip specifically designed to capture CTC clusters from whole, unprocessed blood. The technology, called Cluster-Chip, was developed with support from NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB). The device was described online on May 18, 2015, in Nature Methods.

The Cluster-Chip is designed to allow blood to flow slowly through rows of microscopic triangle-shaped posts. The posts are arranged so that every 2 posts funnel cells toward the tip of a third post. At the tips, single cells—including blood cells and single CTCs—easily slide to either side of the post, continuing to flow through the chip. CTC clusters, however, are captured—they become balanced at the tips of posts between forces gently pulling them in opposite directions. This capture technique is based on the structural properties of CTC clusters rather than on their size or on the presence of particular surface proteins.

Circulating tumor cell cluster. Circulating tumor cell cluster captured by Cluster-Chip.Mehmet Toner, Massachusetts General Hospital

The researchers found that at a blood flow rate of 2.5 milliliters/hour, the chip captured 99% of clusters containing 4 or more cells, 70% of 3-cell clusters, and 41% of 2-cell clusters. To release clusters from the chip, a solution is flowed through the chip in the reverse direction. Examination of the clusters under a microscope showed that the chip preserved the structure of the cell clusters. The technique was significantly more efficient than previous methods of capturing CTC clusters.

The researchers tested the Cluster-Chip in a small trial of 60 people with metastatic cancer. The chip captured CTC clusters in 11 of 27 (41%) breast cancer patients, 6 of 20 (30%) melanoma patients, and 4 of 13 (31%) prostate cancer patients. The team was able to study various aspects of these CTC clusters. The results show that this technique allows for the capture and analysis of CTC clusters from a range of cancer types.

“The presence of these clusters is far more common than we thought in the past,” Toner says. “The fact that we saw clusters in this many patients is really a remarkable finding.”

The researchers also noted the presence of immune cells within certain clusters. Thus, this approach might allow for monitoring of tumor-immune cell interactions.

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References: A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, Engstrom A, Zhu H, Sundaresan TK, Miyamoto DT, Luo X, Bardia A, Wittner BS, Ramaswamy S, Shioda T, Ting DT, Stott SL, Kapur R, Maheswaran S, Haber DA, Toner M. Nat Methods. 2015 May 18. doi: 10.1038/nmeth.3404. [Epub ahead of print]. PMID: 25984697.

Funding: NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB); Stand Up to Cancer; Howard Hughes Medical Institute; Prostate Cancer Foundation; Charles Evans Foundation.