Scientists at the Karolinska Institute along with other colleagues in Sweden have provided new information about the EphA2 receptor, which is associated with cancer. The researchers relied on DNA origami, in which a DNA molecule is shaped into a nanostructure and then used to test theories about cell signaling.

Their study (“Spatial control of membrane receptor function using ligand nanocalipers”) appears in Nature Methods.

It was previously known that the EphA2 receptor played a part in several forms of cancer including breast cancer. The ligand that communicates with the receptor is known as an ephrin molecule. Researchers have been working with the hypothesis that the distance between different ligands—in this case the distance between ephrin molecules—affects the level of activity in the communicating receptor of the adjacent cells.

The Swedish scientists set out to test this hypothesis. They used DNA building blocks to form a stable rod. “We use DNA as the construction material for a tool that we can experiment with,” said Björn Högberg, Ph.D., principal investigator in the department of neuroscience. “The genetic code of the DNA in these structures is less important in this case.”

The team attached ephrins to the DNA rod at various intervals, e.g., 40 or 100 nanometers apart. The DNA rods were then placed in a solution containing breast cancer cells. In the next step, the researchers looked at how active EphA2 was in these cancer cells.

“Using these 'nanocalipers' to present ephrin ligands, we showed that the nanoscale spacing of ephrin-A5 directs the levels of EphA2 receptor activation in human breast cancer cells,” wrote the investigators. “Furthermore, we found that the nanoscale distribution of ephrin-A5 regulates the invasive properties of breast cancer cells. Our ligand nanocaliper approach has the potential to provide insight into the roles of ligand nanoscale spatial distribution in membrane receptor-mediated signaling.”

“For the very first time, we have been able to prove this hypothesis: The activity of EphA2 is influenced by how closely spaced the ligands are on the surrounding cells,” noted Dr. Högberg. “This is an important result in itself, but the point of our study is also that we have developed a method for examining how cells react to nearby cells in a controlled environment, using our custom DNA nanocalipers.”

The researchers describe the cell communication as a form of Braille, where the cells somehow sense the protein patterns of nearby cells, and where the important thing is not only the amount of proteins, but to a great extent the distance between them as well. This study found that a cluster of proteins would communicate more actively than sparsely spaced proteins, even if the concentration was the same.

“This is a model that can help us learn more about the importance of the spatial organization of proteins in the cell membrane to how cells communicate with each other, something that will hopefully pave the way for a brand new approach to pharmaceuticals in the long term,” added Ana Teixeira, a principal investigator at the department of cell and molecular biology. “Today, the function of the pharmaceuticals is often to completely block proteins or receptors, but it is possible that we should rather look at the proteins in their biological context, where the clustering and placement of various proteins are relevant factors for the effect of a drug. This is probably an area where there is important knowledge to obtain, and this is a way of doing it.”

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