Examining Individual Tumor Cells

Despite decades of research into cancer biology, researchers still don’t fully understand what happens to the malignant cells’ DNA as they mutate. It’s not an idle question: The better biologists appreciate how DNA changes, the better they can create therapies that specifically target the disease. Now scientists at Cold Spring Harbor Laboratory, in Cold Spring Harbor, New York, have found a way to get a far more detailed look at a tumor’s biology than was previously possible. James Hicks and his colleagues have shown, for the first time, that it’s possible to examine the genomic evolution of individual cells within a tumor.

By analyzing individual cells taken from different areas of the same breast-cancer tumor, Hicks has shown that a tumor’s landscape can be remarkably variable–different areas of the growth were made up of five very different populations, three of which were cancerous. The result was not completely unexpected, as patients whose original test results indicate their cancer is slow-growing often end up having a very aggressive form of disease. “Everyone looking at the problem is aware of tumor heterogeneity,” or the variation in cell type, Hicks says. “But because there hasn’t been a tool to look at it, it’s been largely ignored.”

Until now, most tumor analysis has been done on samples of thousands of tumor cells–a method that can obscure individual variation and can cause researchers to misidentify a cancer’s aggressiveness. But the technique developed by Hicks and his colleagues allows the researchers to sort and segregate single cells and amplify portions of their genome for analysis. Such a technique is currently too expensive for diagnostics, but they hope that ultimately a fine-needle biopsy could be sent for single-cell analysis to determine the composition of cancer cells in a tumor. Once you know the different populations of cancer cells, you can use therapies that target all of them and eradicate much more of the disease.

“Understanding the cell-to-cell variation in cancer is important for being able to think about cancer treatment,” says Matthew Meyerson, a cancer genomics researcher at the Dana-Farber Cancer Institute and associate professor at Harvard Medical School who was not involved with the study. “[A therapy] has to treat all the cells in a cancer. If there are subpopulations that are resistant to treatment, it won’t be as effective.”

“By showing the DNA can be analyzed at single cell level, Dr. Hicks’s work opens new avenues in the field of molecular analyses of circulating tumor cells,” says Fabrice Andre, a breast-cancer pathologist at the Institut de cancérologie Gustave Roussy in Villejuif, France. “Which means that we will soon be able to have a molecular portrait of breast cancer through a blood sampling.”

While blood-sample diagnostics are likely a little ways down the road, the research is also important for understanding cancer biology at its most basic level. “The evolutionary history of a tumor is written in its genome and provides a fingerprint for following tumor cells wherever they might go in the body,” Hicks says. If researchers can do that, they will be able to glean a deeper understanding how a cancer grows and spreads, and how to stop it.

“Carcinogenesis is a constant process of evolution,” says Larry Norton, medical director of the Evelyn H. Lauder Breast Center at Memorial Sloan-Kettering Cancer Center in New York City, and a frequent collaborator with Hicks. “There are stepwise changes from normal to malignant to even worse malignant states. And this technique actually traces the complex evolution of the carcinogenesis process by looking at the DNA level of single cells.”