MODL-37. MODELING REVERSIBLE TUMORIGENESIS IN CEREBRAL ORGANOIDS

Abstract

Abstract Human cerebral organoids have emerged as a new approach to modeling the role of cancer-associated genes in tumorigenesis ex vivo. Here, we asked whether high-grade tumorigenesis in cerebral organoids is a reversible process. Using inducible cassettes carrying key oncogenic mutations histone H3K27M, dominant negative p53 and activated PDGFRA, we show that their expression in cerebral organoids reproducibly drives high grade malignant transformation in vitro and in vivo, including in orthotopic xenografts. We characterize this transformation as a fusion-negative rhabdomyosarcoma (FN-RMS) phenotype and identify a putative FN-RMS cell-of-origin in cerebral organoids. Finally, we show this transformation is dependent on persistent transgenic oncogene expression, as oncogene withdrawal causes complete tumor regression. These findings demonstrate that cerebral organoids may be used to pinpoint previously unappreciated and distinct roles of different mutations in tumor development and maintenance.