Cluster-Well chip helps to detect metastatic cancer

Cancer spreads via circulating tumour cells (CTCs) that travel through the blood to other organs and are nearly impossible to track. Now researchers at the Georgia Institute of Technology have created a detection method that can show how cancers metastasize and what stage they are, which could lead to earlier and more targeted treatment.

When a tumour starts metastasizing, it sheds its cell into the blood. An individual cell often doesn’t 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 millilitre, and only a handful of those cells would be CTCs in a patient with metastatic cancer. Such intense filtration has been inaccessible using conventional lab methods. Most traditional filtration is too aggressive and would break the cluster back into single cells and ruin the ability to study the effect of a cluster.

“That’s what got engineers like me interested in this, because we are really good at creating sensors, or small devices that actually do sensitive analysis,” said Georgia Tech’s Associate Professor Fatih Sarioglu. “We started developing technologies to catch these precious cells to help manage cancer better.”

Sarioglu’s lab invented a new type of chip called the 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’s cancerous.

“Microfluidic chips give you more control as a designer to actually ask whatever question that you want to ask those cells,” Sarioglu said. “It increases the precision 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 rapidly process a clinically relevant volume of blood, the researchers relied on membrane filtration to make the chip operation more scalable. In effect, the chip looks like a standard membrane filter, but under an electron microscope the microfluidic chip reveals its delicate structure used to capture clusters while letting other blood cells pass through. The chip is initially fabricated with silicon just like a central processing unit in a computer, but it is later transferred to polymers to make it accessible, affordable and single-use, while still retaining its delicacy and precision.

“We really created only the traps that we need to have for recognising the clusters with the microfluidic chip, and the rest is just a standard filter holder,” Sarioglu said. “Compared to a conventional microfluidic chip, you will get a much more practical assay with orders of magnitude improvement in throughput and a higher sensitivity.”

The researchers used the chip to screen blood samples from patients with ovarian or prostate cancers through a partnership with the 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 analyse a subset, publishing their results in the journal Nature Communications.

The chip’s design means CTC clusters are filtered in microwells and can later be accessed for further analysis. Even a single CTC can contain a significant amount of data on the patient and their specific cancer, which can be critical for managing the disease. For example, the researchers noted hundreds of CTCs in clusters in the blood of ovarian cancer patients, some still alive — a finding that could be consequential to the spread of the disease.

Also, by sequencing the RNA in prostate CTC clusters isolated by the chip, the researchers identified specific genes expressed by these metastasizing cells. Importantly, CTC clusters from different patients were shown to express different genes, which can be potentially utilised to develop personalised, targeted therapies. Sarioglu envisions Cluster-Wells as being a routine part of the treatment process to determine what stage the cancer is at from a simple blood draw.

“Finding these clusters was very elusive,” Sarioglu said. “But this is a technology that allows these precious circulating tumour cell clusters virtually in any cancer to be accessed with precision and practicality that has not been possible before.”

Image caption: Fabrication of the microchip. The device is fabricated by injecting a polymer into a micro-fabricated mould and the polymer is cured under ultraviolet light to produce low-cost, single-use devices.

Please follow us and share on Twitter and Facebook. You can also subscribe for FREE to our weekly newsletters and bimonthly magazine.