New chip could lead to targeted, earlier treatments for metastatic cancer

The cancer spreads via circulating tumor cells (CTCs) that travel through the blood to other organs, and they are nearly impossible to track. Now, researchers at the Georgia Institute of Technology have found a detection method that could revolutionize cancer treatment by showing how cancers metastasize and what stage they are in. This could lead to earlier and more targeted treatment, starting with a simple blood test.

When a tumor begins to metastasize, it releases its cell into the blood. A single cell often does not survive the bloodstream on its own, but clusters of cells are much more robust and can travel to other organs, effectively pushing the cancer to a metastatic state.

CTCs have proven difficult to study, let alone treat. Blood contains billions of cells per milliliter, and only a handful of these cells would be CTCs in a patient with metastatic cancer. Such intense filtration has been unattainable using conventional laboratory methods. Most traditional filtrations are too aggressive and would split the cluster into individual cells and ruin the ability to study the effect of a cluster.

“That’s what sparked the interest of engineers like me, because we’re really good at creating sensors or small devices that do sensitive analysis,” said Fatih Sarioglu, associate professor at the School of Electrical Engineering. and computing. “We have begun to develop technologies to capture these valuable cells to better manage cancer.”

Sarioglu presented the research in “High-Throughput, Label-Free Isolation of Circulating Tumor Cell Clusters in Meshed Microwells,” recently published in Nature Cocommunications.

Creation of the Cluster-Well

Sarioglu’s lab has invented a new type of chip called Cluster-Well, combining the precision of microfluidic chips with the efficiency of membrane filtration to find CTC clusters. Using micron-sized features, microfluidic chips can precisely locate each cell in a blood sample and determine if it is cancerous.

“Microfluidic chips give you more control as a designer to ask the question you want to ask these cells,” Sarioglu said. “It increases accuracy and sensitivity, which is what you need for an application like this because you want to find that single cell out of many blood cells.”

To quickly process a clinically relevant volume of blood, the researchers relied on membrane filtration to make the chip’s operation more scalable. Indeed, the chip looks like a standard membrane filter, but under an electron microscope, the microfluidic chip reveals its delicate structure used to capture clumps while letting other blood cells through.

Convenience was just as important as functionality for researchers. Although the chip is initially made with silicon, much like a central processing unit in a computer, it is later transferred to polymers to make it accessible, affordable, and single-use, while maintaining its delicacy and precision.

“We really only created the traps we need to recognize clusters with the microfluidic chip, and the rest is just a standard filter holder,” Sarioglu said. “Compared to a conventional microfluidic chip, you’ll get a much more convenient test with orders of magnitude of improved throughput and higher sensitivity.”

Analysis of patient tumor cell clusters

The researchers used the chip to screen blood samples from patients with ovarian or prostate cancer through a partnership with Emory and Northside hospitals. They isolated CTC clusters ranging from two to 100 or more cells from prostate and ovarian cancer patients and used RNA sequencing to analyze a subset.

The unique chip design means that CTC clusters are filtered into microwells and can then be viewed for further analysis. Even a single CTC can contain a significant amount of data about the patient and their specific cancer, which can be essential for disease management. For example, researchers noted hundreds of CTC clusters in the blood of ovarian cancer patients, some still alive, a finding that may be secondary to the spread of the disease.

Also, by sequencing the RNA in clusters of prostate CTCs isolated by the chip, the researchers identified specific genes expressed by these metastasizing cells. Importantly, CTC clusters from different patients express different genes, which can potentially be used to develop personalized and targeted therapies. Sarioglu sees Cluster-Wells as an integral part of the treatment process to determine the stage of the cancer from a simple blood test.

“Finding these clusters was very elusive,” Sarioglu said. “But this is a technology that makes it possible to access these precious clumps of circulating tumor cells in virtually any cancer with a precision and convenience that was not possible before.”

Reference: Boya M, Ozkaya-Ahmadov T, Swain BE, et al. High-throughput, label-free isolation of circulating tumor cell clusters in mesh microwells. Nat Common. 2022;13(1):3385. do I: 10.1038/s41467-022-31009-9

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