Molecular Mechanisms of Altered DNA Binding and Chromatin Regulation by Oncogenic Fusions in Ewing Sarcoma
Ewing sarcoma is an aggressive cancer in children, teenagers, and young adults. Treatment involves intensive chemotherapy, surgery, and/or radiation, including disfiguring surgeries. Many survivors experience long-term side effects. Despite aggressive treatment, the disease is cured in only about 50% of patients, highlighting the urgent need for better, less toxic therapies. One of the biggest challenges in developing new treatments is that we still don’t fully understand what causes Ewing sarcoma at the molecular level. More than 30 years ago, scientists discovered a chimeric (or "fusion") protein called EWSR1::FLI1 that drives this cancer. Although this protein has been studied extensively, we still don’t understand exactly how it works. A major barrier has been that EWSR1::FLI1 is extremely difficult to isolate and study in the lab. Our team has recently overcome this challenge by developing a method to purify the full protein, allowing us to begin asking important new questions. Our early results suggest that the two parts of the protein, one each from EWSR1 and FLI1, don’t just function independently, but interact in unexpected ways that may explain how the protein causes cancer. This proposal begins to answer those questions. Understanding how this fusion protein works at the molecular level is essential for designing targeted therapies, and our ultimate goal is to use this knowledge to create better drug screening tools that reflect the unique biology of EWSR1::FLI1.
Project Goals
This project aims to understand how the main driver of Ewing sarcoma, the EWSR1::FLI1 protein,causes cancer, and use this knowledge to develop better ways to find drugs that specifically target it. EWSR1::FLI1 is a chimeric protein, made from pieces of two separate proteins: EWSR1 and FLI1. Our recent publications and new data show that EWSR1::FLI1 behaves very differently from either EWSR1 or FLI1 alone. Instead of acting like a sum of its parts, the two halves of the protein interact in complex and surprising ways, giving rise to new properties that promote cancer. Until now, one of the biggest obstacles in studying EWSR1::FLI1 has been the difficulty of producing enough of the protein to study it in detail. We have overcome this barrier and can isolate large quantities of pure, active protein for laboratory analysis. This breakthrough allows us to ask new and important questions about how the protein works. Here we will study how the two halves of EWSR1::FLI1 work together in cancer cells. Our first aim focuses on how the protein binds to DNA, and our second aim investigates how it alters the 3D structure of DNA in the cell. In both aims, we use what we’ve learned to create new lab tests that reflect the unique behavior of EWSR1::FLI1—tools that are essential for screening drugs that target this fusion protein. This research is critical for understanding the biology of Ewing sarcoma and will lay the foundation for developing more effective, targeted therapies.
