The protein EPHA2, a receptor on the lining of blood vessels, controls how breast cancer cells metastasize around the body. These findings, from a study on breast cancer cell lines recently published in Science Signaling, sheds light on how cancer cells exit the blood vessels to enter a new part of the body.1

When tumor cells metastasize, they first enter the blood stream and attach to the inner walls, or lining, of blood vessels. To push their way out of the blood vessels, this study found that the tumor cells control the receptor protein EPHA2.

EPHA2 is activated when cancer cells remain inside the blood vessels, and its inactive form allows the cancer cells to push out and spread. It becomes inactivated through phosphorylation, the process of a phosphate molecule binding to a specific site of the EPHA2 protein.

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When the dynamics of phosphorylating EPHA2 are altered, metastasis is more likely. Targeting the phosphorylation process may be a fruitful research area for controlling metastasis. The researchers used a highly metastatic breast cancer cell line that targets the lung to explore EPHA2 and its phosphorylation; the breast cancer cells enhanced phosphorylation of EPHA2 at a specific site. The researchers identified the altered phosphorylation dynamics of EPHA2 as a mechanism that may enhance breast cancer cells’ exit from the bloodstream.

“The next step is to figure out how to keep this receptor switched on, so that the tumor cells can’t leave the blood vessels: stopping breast cancer spreading and making the disease easier to treat successfully,” said Claus Jørgensen, PhD, who led the research at The Institute of Cancer Research, London, and at Cancer Research UK’s Manchester Institute at the University of Manchester in the United Kingdom, and is the corresponding author of the study.

Nell Barrie, Cancer Research UK’s senior science information manager, said, “This is important research that teaches us more about how breast cancer cells move. Research like this is vital to help our understanding of how cancer spreads, and how to stop this from happening. More research is needed before this will benefit patients but it’s a jump in the right direction.”

The study was funded by Cancer Research UK.


1. Locard-Paulet M, Lim L, Veluscek G, et al. Phosphoproteomic analysis of interacting tumor and endothelial cells identifies regulatory mechanisms of transendothelial migration. Sci Signal. 2016;9(414):ra15.