Tumor profile
A chip has been created that splits cancer cells
Maxim Pridanov, FutureOut
Drawings from the University of Michigan Blood biopsy press release: New technique enables detailed genetic analysis of cancer cells – VM.
Genetic profiling of cancer cells can help doctors target tumors and monitor treatment more effectively. The new method is a significant improvement over current approaches, as it also identifies differences between cancer cells in a single patient.
"It could be a completely different game," says Max Wicha, professor of oncology at University of Michigan and senior physician of a study published in Nature Communications (Cheng et al., Hydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells).
Previous methods meant a compromise between a comprehensive genetic profile of a limited subset of cancer cells or capturing most cancer cells and being able to search for only a few genes. As a result, genetic profiles have often neglected important populations of cancer cells, including those thought to spread cancer in the body.
"Our chip allows us to capture clean circulating tumor cells and then extract genetic information without any contamination from red and white blood cells," says the head of the work, Yusik Yun, professor of electrical engineering and computer science at the University of Michigan.
A new laboratory chip called Hydro-Seq, slightly larger than a coin, allows for a comprehensive genetic study of cancer based on a blood test.
Many modern cancer drugs work by chasing cells with certain genes. These genes allow us to identify them as cancer cells. But they are not equally active in the patient's cancer cell population and may change during the course of treatment.
Repeated biopsies to monitor the tumor are painful and potentially dangerous for the patient. Taking cancer cells from blood samples offers a non-invasive way to observe whether the cancer disappears or becomes resistant to treatment.
"This allows not only to choose the target therapy, but also to monitor the results of this therapy in patients when performing this blood test," says Uicha.
Using this method, the team collected and analyzed 666 cancer cells from the blood of 21 breast cancer patients.
A cancer cell (red) that Hydro-Seq took from a blood sample.
Genetic analysis has confirmed that even in one patient, cancer cells often behave differently. Wyche's group has previously shown that cancer cells with stem cell properties mediate metastasis.
Although cancer stem cells make up only a few percent of tumor cells, they make up a higher proportion of cancer cells in the bloodstream. In this study, about 30-50 percent of the cancer cells sampled from blood samples showed stem-like properties.
This population is particularly easy to miss with methods that take clean but incomplete samples of cancer cells from a patient's blood by capturing proteins on the cell surface. Stem-like cells are in the spectrum between two more typical cell types, which means that they do not show consistent protein markers.
To get a clean and unbiased set of cancer cells from a blood test tube, the team started with a technique that removes blood cells by sorting a blood sample by cell size. Starting with about one cancer cell in a billion blood cells, this step left only 95 or so blood cells for each cancer cell. But it's still too polluted for detailed genetic analysis.
The new method, which the researchers call Hydro-Seq, gets rid of the last blood cells and then analyzes each cell.
The key technology is a chip with a system of channels and cameras. It captures cancer cells one by one, passing fluid through the drainage in each chamber, and then closes it when a cancer cell comes across. As soon as the chamber is clogged, the cells in the channel pass by and are sucked into the next chamber. Then, in order to "flush" the blood cells from the chip, they passed clean liquid through the chip and pulled it out again, taking with them almost all the other polluting cells.
With a clean sample of isolated cancer cells, the team made genetic profiles. They followed the cells' "transcriptomes"–essentially snapshots of which DNA each cell read and used. This revealed the active genes of the cells.
The researchers captured transcriptomes using barcodes, a technique that until now has been difficult to use with small cell samples. The team threw a barcode ball into each chamber and then closed the chambers before destroying the cell membranes. This released the RNA–small pieces of genetic code recently read from the DNA of the cell– so that the RNA attached itself to the barcoded genetic code on the ball. The team can then analyze the contents of each cell individually.
"Previously, we could measure two or three genes simultaneously using staining techniques, but now we get an exhaustive picture of circulating tumor cells by measuring thousands of genes in each cell at a time," says first author Yu–Chi Chen, a research assistant in electrical engineering and computer science.
Cancer treatment is like hunting for a moving target, with cancer altering its gene expression because drugs kill some cells, but not others. Co-author Monica Burness, associate professor of internal medicine, expects to use the new device to track patients' progress in an upcoming drug trial.
"It's a very powerful tool for monitoring – at the cellular level – what treatment does to tumors over time," says Berness, who is researching new drugs for cancer patients.
Funding for this work came from the National Institutes of Health, the Breast Cancer Research Foundation, the Forbes Institute for Cancer Research and University of Michigan Colter Research and Broadcast Partnership Programs. The researchers manufactured the devices at the Lurie nanotechnology factory.
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