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

通过激活染色体 3D 超级增强子相互作用和基因组不稳定性来模拟胚胎神经母细胞瘤肿瘤发生

• 批准号: 508001742
• 负责人: Professor Dr. Carl Herrmann
• 金额: --
• 依托单位: Abteilung Neuroblastom-Genomik
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/508001742?language=en
• 关键词: Modeling; embryonal; neuroblastoma; tumorigenesis; activation

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.

人类胚胎神经母细胞瘤是一种聚集性肿瘤，被认为是反复发生的结构性染色体改变(如易位、基因扩增)导致癌基因激活的结果。增强子劫持事件是指控制细胞识别基因的强调控区域(超级增强子，SE)被带到癌基因(如MYCN、MYC、TERT)附近，是定义高度侵袭性神经母细胞瘤亚型的反复特征。最近关于神经母细胞瘤进化的研究表明，这些肿瘤发生在胚胎发育过程中的神经母细胞群体中，通常会产生肾上腺髓质细胞。在这里，我们将检验一种假设，即在起源细胞(S)中，沿着正常发育轨迹发生广泛的3D染色体变化的状态(例如顺式/反式相互作用比的变化)容易在基因组不稳定的背景下导致结构染色体的变化。我们将定义生理时间分辨的表观遗传状态和正常肾上腺发育过程中的3D交互作用，并通过实验诱导神经母细胞特异性3D交互作用和基因组不稳定性，从功能上概括HiPSC来源的神经母细胞中神经母细胞瘤的发生。总之，我们的研究将开发一种新的胚胎肿瘤发生的分子框架，它依赖于自然发生的结构重排，这将是更准确的胚胎肿瘤模型的基础。