Study reveals new dual role of ezrin in osteosarcoma

Scientists at Georgetown University’s Lombardi Comprehensive Cancer Center have discovered a new dual function for a well-known cancer-related protein called ezrin. The discovery could potentially open the door to new treatments for osteosarcoma, the most common bone cancer in children and young adults, as well as other ezrin-dependent cancers.

The findings were published in the journal on March 17, 2026 Science notation.

For decades researchers believed that ezrin was active only in its open form in the cell membrane. Its closed form found in the interior of the cell was considered inactive or dormant.

As we learn more about the inner workings of cancer cells based on laboratory and animal studies, that knowledge often translates into new and better treatment options for patients. “Our research on ezrin’s dual role in promoting cancer is an example of how basic research plays a major role in helping reduce cancer mortality.”

Aykut Uren, MD, professor, department of oncology and the departments of biochemistry and molecular and cellular biology at Georgetown, and corresponding author of the published study

Each year, approximately 1,000 new cases of osteosarcoma are diagnosed in the United States. About half of these are children and teenagers. Five-year survival rates, when osteosarcoma is caught early and has not spread, is between 60-75%. However, if the disease metastasizes, survival rates drop to 5–30%. These are the metastatic cases that have been the most difficult to treat.

One aspect of the scientists’ innovative experiments was on zebrafish. Because ezrin rotates between open and closed states, it is difficult to study the function of each state separately because there is always a mixture of both conformational states. Therefore, with the aid of sophisticated genetic techniques, scientists created a set of osteosarcoma cells that did not express any ezrin protein and transplanted them into zebrafish to study their ability to metastasize. They then reintroduced two mutant forms of ezrin; One is closed in the open state, the other is closed in the closed state. This allowed him to study the function of open and closed forms alone without the interference of the other.

Uren and his colleagues found that caged ezrin binds directly to RNA. These RNA interactions allow ezrin to influence how genes are translated into proteins – functions that ultimately support cancer cell growth and metastasis.

Of most concern was the finding that the silenced form of ezrin could restore metastatic behavior in osteosarcoma cells that lack ezrin. The dual role of ezrin 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.

Uren says, “These findings fundamentally change the way we think about ezrin. We now know that the closed form of ezrin is not inactive at all – it is performing essential RNA-related functions that help cancer cells spread.” “By revealing that cleaved ezrin is an active RNA-binding protein, we have identified an entirely 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. Uren says the good news is that his research lab has already identified small molecules that can block both the open and closed states of ezrin. They have shown promise in cultured osteosarcoma cells in the laboratory and in several mouse models. But the researchers’ next challenge is to work to improve the drug’s binding properties and solubility before considering potential trials in people.

In addition to Uren, Georgetown writers include Emre Deniz, Prakriti Tiwari, Purushottam B. Tiwari, Eric Glasgow, Brent T. Harris, Chunyan Hou, Junfeng Ma and Jeffrey Toretzky. Anoop Tiwari is at Walter Johnson High School, Bethesda, Maryland.

Uren and his co-authors report that they have no personal financial interests related to the study.

This work was funded by a grant from the Children’s Cancer Foundation in Baltimore.