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

人类胚胎性神经母细胞瘤是一种典型的肿瘤，被认为是复发性染色体结构改变（如易位、基因扩增）导致癌基因激活的结果。增强子劫持事件，即控制细胞特性基因的强调控区域（超级增强子，se）被带到癌基因（如MYCN， MYC， TERT）的附近，是定义高度侵袭性神经母细胞瘤亚型的复发性特征。最近关于神经母细胞瘤进化的研究表明，这些肿瘤出现在胚胎发生的神经母细胞群体中，通常会产生肾上腺髓质细胞。在这里，我们将验证一个假设，即在基因组不稳定的背景下，起源细胞沿正常发育轨迹广泛的3D染色体变化状态（例如顺式/反式相互作用比率的变化）易导致染色体结构改变。我们将定义正常肾上腺发育过程中生理时间解决的表观遗传状态和3D相互作用，并通过实验诱导神经母细胞特异性3D相互作用和基因组不稳定性，在hipsc衍生的神经母细胞中功能性概括神经母细胞瘤的发生。总之，我们的研究将为胚胎肿瘤发生建立一个新的分子框架，它依赖于自然发生的结构重排，这将为更准确的胚胎肿瘤模型奠定基础。

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.