WASHINGTON — Scientists at Georgetown University’s Lombardi Comprehensive Cancer Center have uncovered a new dual function for a well-known cancer-related protein called ezrin. This finding could potentially open the door to new treatments for osteosarcoma, the most common bone cancer in children and young adults, as well as other cancers that are ezrin-dependent.
The finding appeared March 17, 2026, in the journal Science Signaling.
For decades researchers believed that ezrin was only active in its open form at the cell membrane. Its closed form, found in the cell’s interior, was thought to be inactive or dormant.
“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,” says Aykut Üren, MD, professor in the Department of Oncology and the Department of Biochemistry and Molecular & Cellular Biology at Georgetown, and corresponding author of the published study. “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.”
Each year, about 1,000 new cases of osteosarcoma are diagnosed in the United States. About half of these are in children and adolescents. Five-year survival rates, when osteosarcomas are caught early and haven’t spread, range from 60–75%. However, if the disease metastasizes, survival rates drop to 5–30%. It is these metastatic cases that have been the most difficult to treat.
One aspect of the scientists’ innovative experiments was in zebrafish. Because ezrin pivots between open and closed states, it is difficult to study the function of each state separately as there is always a mixture of both conformational states. So, with the aid of sophisticated genetic techniques, the scientists created a set of osteosarcoma cells that did not express any ezrin protein and implanted them into zebrafish to study their ability to metastasize. They then reintroduced two mutant forms of ezrin; one locked in the open state, the other locked in the closed state. That allowed them to study the function of open and closed forms alone without the interference of the other.
Üren and his colleagues found that closed ezrin binds directly to RNA. These RNA interactions allow closed ezrin to influence how genes are translated into proteins — functions that ultimately support cancer cell growth and metastasis.
Most concerning was the finding that the closed form of ezrin can restore metastatic behavior in osteosarcoma cells that lack ezrin. Ezrin’s dual role may help explain why it has been such a powerful driver of metastasis in osteosarcoma and other tumors and why targeting it has been challenging.
“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,” says Üren. “By revealing that closed ezrin is an active RNA-binding protein, we’ve identified a completely new angle for therapeutic development.”
The investigators hope that if future efforts find a way to disrupt ezrin’s interaction with RNA, they may be able to slow or prevent metastasis. The good news, says Üren, is his research lab has already identified small molecules that can inhibit both open and closed states of ezrin. They have shown promise in cultured osteosarcoma cells in the lab and in multiple mouse models. But the researcher’s next challenge is to work to improve the drug's binding properties and solubility before they can consider possible tests in people.
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In addition to Üren, authors at Georgetown include Emre Deniz, Prakriti Tiwari, Purushottam B. Tiwari, Eric Glasgow, Brent T. Harris, Chunyan Hou, Junfeng Ma and Jeffrey Toretsky. Anup Tiwari is at Walter Johnson High School, Bethesda, Maryland.
Üren and his co-authors report having no personal financial interests related to the study.
This work was funded by a grant from the Children’s Cancer Foundation in Baltimore.
Science Signaling
Experimental study
Animals
The unphosphorylated, closed form of ezrin binds to RNA to maintain a metastatic phenotype in osteosarcoma cells
17-Mar-2026