Decoding fusion oncoprotein-driven protein interaction landscapes to reveal therapeutic vulnerabilities in pediatric ependymoma
Ependymoma is a severe childhood brain tumor that often cannot be cured with current treatments. Children typically undergo surgery and radiation, which can help manage the cancer but often cause long-term side effects. Unfortunately, there are no medicines that specifically target the biology of this cancer, and many children experience tumor regrowth even after aggressive treatment. Most ependymomas in the upper part of the brain are caused by a genetic error where two genes are abnormally fused together, creating what is called a fusion oncoprotein. This “fusion protein” sends harmful signals within the cell that alter which genes are turned on or off, promoting tumor growth. However, we still do not fully understand how these fusion proteins function inside the cell or which other proteins they interact with. Scientists now have evidence that these fusion proteins gather in small “droplets” inside the cell’s nucleus—called biomolecular condensates—where they recruit many other proteins to help control gene activity. If we can identify which proteins are pulled into these droplets, we might find new weak points that can be targeted with drugs. Understanding these networks is an essential step toward developing better, safer treatments for children with ependymoma.
Project Goals
The goal of this project is to understand how fusion proteins that cause ependymoma work within tumor cells and to identify new treatment approaches based on these findings. To do this, we will attach a special enzyme called TurboID to the fusion proteins. TurboID functions like a “molecular highlighter,” marking nearby proteins inside the cell. This allows us to map all the proteins that gather around the fusion protein, especially within abnormal droplets (condensates) where it operates. Once we identify which proteins are part of this network, we will test which ones the tumor actually depends on for growth. We will deactivate these partner proteins one at a time to see if the cancer cells stop growing or die. We will also evaluate drugs or small molecules to determine if disrupting these interactions could serve as a new therapy. By creating the first detailed map of these fusion-driven protein networks and identifying their vulnerabilities, this study aims to pave the way for more precise and effective treatments for children facing ependymoma.
