Mentor Name: Elvin Wagenblast

Pediatric hepatoblastoma is the most common malignant liver cancer in young children and remains a life-threatening disease for patients with advanced or relapsed tumors. While survival rates are high for children with localized disease, outcomes for patients with metastatic, recurrent, or chemotherapy-resistant hepatoblastoma are poor, and there are currently no targeted therapies available for these high-risk patients. A major barrier to therapeutic progress is the lack of developmentally relevant humanized experimental models that faithfully capture the early cellular and molecular events driving hepatoblastoma initiation. Hepatoblastoma is thought to arise from hepatoblasts, immature liver progenitor cells present during early development, and is frequently associated with genetic alterations that disrupt key developmental signaling pathways, cellular stress responses, and cell-cycle regulation. Although these disease-associated pathways have been studied in animal models, humanized systems that allow controlled interrogation of how oncogenic alterations transform hepatoblasts remain limited. The goal of this project is to develop a humanized experimental model of pediatric hepatoblastoma using human hepatoblast-like cells. Building on prior work in our laboratory, I will establish hepatoblast-like cells and introduce hepatoblastoma-associated genetic alterations using CRISPR/Cas9-mediated genome editing delivered by electroporation. These perturbations will be used to assess whether defined genetic alterations are sufficient to drive early malignant transformation in a human developmental context. This project will establish a scalable platform to study hepatoblastoma initiation and will lay the groundwork for future efforts to identify therapeutic vulnerabilities specific to pediatric liver cancer, with the ultimate goal of improving outcomes for children affected by this disease.