Vasileva Elena, Arata Claire, Luo Yongfeng, Burgos Ruben, Crump J Gage, Amatruda James F
Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027 USA.
Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
bioRxiv. 2024 Oct 29:2024.10.27.620438. doi: 10.1101/2024.10.27.620438.
Ewing sarcoma is a malignant small round blue cell tumor of bones and soft tissues caused by chromosomal translocations that generate aberrant fusion oncogenes, most frequently EWSR1::FLI1. The cell of origin and mechanisms of EWSR1::FLI1-driven transformation have remained unresolved, largely due to lack of a representative animal model. By developing a zebrafish Ewing sarcoma model, we provide evidence for a neural crest origin of this cancer. Neural crest-derived cells uniquely tolerate expression of EWSR1::FLI1 and targeted expression of EWSR1::FLI1 in these cells generates Ewing sarcomas. Single-cell analysis of tumor initiation shows that EWSR1::FLI1 reprograms neural crest-derived cells to a mesoderm-like state, strikingly resulting in ectopic fins throughout the body. By profiling chromatin accessibility and genome-wide EWSR1::FLI1 binding, we find that the fusion oncogene hijacks developmental enhancers for neural crest to mesoderm reprogramming during cancer initiation. These findings show how a single mutation profoundly alters embryonic cell fate decisions to initiate a devastating childhood cancer.
尤因肉瘤是一种发生于骨骼和软组织的恶性小圆蓝细胞肿瘤，由染色体易位导致异常融合癌基因引起，最常见的是EWSR1::FLI1。其起源细胞以及EWSR1::FLI1驱动的细胞转化机制一直未得到解决，主要是由于缺乏具有代表性的动物模型。通过建立斑马鱼尤因肉瘤模型，我们为这种癌症的神经嵴起源提供了证据。神经嵴来源的细胞独特地耐受EWSR1::FLI1的表达，并且在这些细胞中靶向表达EWSR1::FLI1会产生尤因肉瘤。对肿瘤起始的单细胞分析表明，EWSR1::FLI1将神经嵴来源的细胞重编程为中胚层样状态，显著导致全身出现异位鳍。通过分析染色质可及性和全基因组EWSR1::FLI1结合情况，我们发现融合癌基因在癌症起始过程中劫持了神经嵴向中胚层重编程的发育增强子。这些发现揭示了单个突变如何深刻改变胚胎细胞命运决定，从而引发一种毁灭性的儿童癌症。
