Modeling embryonal neuroblastoma tumorigenesis by activation of chromosomal 3D super enhancer interactions and genomic instability

Human embryonal neuroblastoma is a paradigmatic tumor that is thought to develop as a consequence of recurrent structural chromosomal alterations (e.g. translocations, gene amplifications) leading to oncogene activation. Enhancer hijacking events, where strong regulatory regions (super enhancers, SEs) controlling cell identity genes are brought into close proximity of oncogenes (e.g., MYCN, MYC, TERT), are recurrent features defining highly aggressive neuroblastoma subtypes. Recent studies on neuroblastoma evolution indicate that these tumors arise during embryogenesis in a neuroblast population that usually gives rise to adrenal medullary cells. Here, we will test the hypothesis that states of extensive 3D chromosomal changes along the normal developmental trajectory (e.g. changes in cis/trans interaction ratio) in the cell(s) of origin predispose to structural chromosomal alterations in the context of genomic instability. We will define physiological time-resolved epigenetic states and 3D interactions during normal adrenal gland development and functionally recapitulate neuroblastoma tumorigenesis in neuroblasts derived from hiPSCs by experimentally inducing neuroblast-specific 3D interactions and genomic instability. In summary, our studies will develop a new molecular framework for embryonal tumorigenesis that relies on naturally occurring structural rearrangements and that will be the foundation for more accurate embryonal tumor models.