Xu Yunyun, Lou Daohua, Chen Ping, Li Gang, Usoskin Dimtry, Pan Jian, Li Fang, Huang Shungen, Hess Caroline, Tang Ruze, Hu Xiaohan, Yu Juanjuan, Arceo Maria, de Krijger Ronald R, Tischler Arthur S, Schlisio Susanne, Ernfors Patrik, Hu Yizhou, Wang Jian
Pediatric Clinical Research Institute, Children's Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215000, China.
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17165, Sweden.
Dev Cell. 2025 Sep 8;60(17):2248-2263.e11. doi: 10.1016/j.devcel.2025.04.013. Epub 2025 May 9.
Neuroblastoma, the most prevalent extracranial pediatric solid tumor, arises from neural crest progeny cells. It exhibits substantial developmental plasticity and intratumoral heterogeneity, leading to survival rates below 50% in high-risk cases. The regulatory mechanisms underlying this plasticity remain largely elusive. In this integrative study, we used single-cell MultiOmics from a mouse spontaneous tumor model and spatial transcriptomics from human patient samples to dissect the transcriptional and epigenetic landscapes that govern developmental states in neuroblastoma. We identified developmental intermediate states in high-risk neuroblastomas critical for malignant transitions and uncovered extensive epigenetic priming with latent capacity for diverse state transitions. Furthermore, we mapped enhancer gene regulatory networks (eGRNs) and tumor microenvironments sustaining these aggressive states. State transitions and malignancy could be interfered with by targeting transcription factors controlling the eGRNs.
神经母细胞瘤是最常见的儿童颅外实体瘤，起源于神经嵴祖细胞。它表现出显著的发育可塑性和肿瘤内异质性，导致高危病例的生存率低于50%。这种可塑性背后的调控机制在很大程度上仍不清楚。在这项综合研究中，我们使用了来自小鼠自发肿瘤模型的单细胞多组学技术和来自人类患者样本的空间转录组学技术，来剖析控制神经母细胞瘤发育状态的转录和表观遗传景观。我们在高危神经母细胞瘤中确定了对恶性转变至关重要的发育中间状态，并发现了具有多种状态转变潜能的广泛表观遗传预激发。此外，我们绘制了维持这些侵袭性状态的增强子基因调控网络（eGRNs）和肿瘤微环境。通过靶向控制eGRNs的转录因子，可以干扰状态转变和恶性肿瘤进程。
