Grant: Project Grant

Osteosarcoma (OS) is a rare but aggressive bone cancer that mainly affects children and young adolescents. While chemotherapy has improved survival rates, patients whose tumors do not respond well or have already spread at diagnosis face poor outcomes. Scientists have recently begun exploring how changes in gene regulation-beyond DNA mutations-may drive OS progression. These changes, known as epigenetic modifications, can alter how genes are turned on or off without changing the underlying DNA sequence. One key regulator of gene activity is the Polycomb Repressive Complex 2 (PRC2), which plays a role in keeping certain genes switched off when they are not needed. PRC2 does this through a protein called EZH2, which adds a chemical mark to DNA-associated proteins called histones. In some cancers, including OS, this regulatory system can be disrupted. Our research found that a specific protein, EZHIP, is abnormally increased in many OS cases, leading to changes in PRC2 function and making tumors more aggressive. Additionally, we identified recurrent mutations in histone H3 (G34) that may also contribute to OS development and resistance to treatment. This project aims to uncover how these epigenetic alterations help OS grow and spread. Using advanced gene-editing tools and experimental models, we will identify weaknesses in OS cells that rely on these changes. We will then test drugs that target these vulnerabilities to develop new treatment strategies. By understanding how epigenetic changes drive OS, this research may lead to new, more effective therapies, particularly for patients with aggressive or treatment-resistant disease. Ultimately, our goal is to improve outcomes and provide better, more personalized treatment options for young OS patients.