Scientists at Georgetown University's Lombardi Comprehensive Cancer Center reported on Mar. 17 that they have discovered a new dual function for the cancer-related protein ezrin, which could lead to new treatments for osteosarcoma and other cancers dependent on this protein.
Osteosarcoma is the most common bone cancer in children and young adults. The discovery is significant because it may help explain why targeting ezrin has been challenging and could provide a new approach to slowing or preventing metastasis, which remains difficult to treat.
For years, researchers believed that only the open form of ezrin at the cell membrane was active, while its closed form inside the cell was considered inactive. However, Aykut Üren, MD, professor at Georgetown and corresponding author of the study published in Science Signaling, said: "As we know more about the inner working of cancer cells based on laboratory and animal studies, that knowledge often translates to new and better treatment options for patients. Our research into the dual role of ezrin in driving cancer is an example of how basic research plays a major role in helping decrease cancer mortality."
The team used genetic techniques to create osteosarcoma cells without any ezrin protein and implanted them into zebrafish. They then reintroduced mutant forms of ezrin locked in either open or closed states to study their functions separately. The researchers found that closed ezrin binds directly to RNA and influences gene translation into proteins—functions supporting cancer growth and metastasis. Notably, closed ezrin alone could restore metastatic behavior in cells lacking normal ezrin.
Üren said: "These findings fundamentally change how we think about ezrin. We now know that ezrin's closed form is not inactive at all - it's performing essential RNA-related functions that help cancer cells spread. By revealing that closed ezrin is an active RNA-binding protein, we've identified a completely new angle for therapeutic development." His lab has already identified small molecules capable of inhibiting both forms of ezrin with promising results in lab cultures and mouse models; however, further work is needed before considering human trials.
The study involved additional authors from Georgetown as well as a contributor from Walter Johnson High School in Bethesda, Maryland. The authors reported no personal financial interests related to the study. Funding was provided by a grant from the Children's Cancer Foundation in Baltimore.
