Institut Curie Research Center, Paris Sciences et Lettres (PSL) Research University, INSERM U830, 75005 Paris, France; Institut Curie, Paris Sciences et Lettres (PSL) Research University, Medical Oncology Department, 75005 Paris, France.
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Rep. 2023 Jan 31;42(1):112013. doi: 10.1016/j.celrep.2023.112013. Epub 2023 Jan 18.
Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that lack functional validation. An example is the fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implement a cross-species comparative oncology approach with zebrafish, mouse allograft, and patient samples. We find that VGLL2-NCOA2 is sufficient to generate mesenchymal tumors that display features of immature skeletal muscle and recapitulate the human disease. A subset of VGLL2-NCOA2 zebrafish tumors transcriptionally cluster with embryonic somitogenesis and identify VGLL2-NCOA2 developmental programs, including a RAS family GTPase, ARF6. In VGLL2-NCOA2 zebrafish, mouse, and patient tumors, ARF6 is highly expressed. ARF6 knockout suppresses VGLL2-NCOA2 oncogenic activity in cell culture, and, more broadly, ARF6 is overexpressed in adult and pediatric sarcomas. Our data indicate that VGLL2-NCOA2 is an oncogene that leverages developmental programs for tumorigenesis and that reactivation or persistence of ARF6 could represent a therapeutic opportunity.
临床测序工作正在迅速鉴定缺乏功能验证的肉瘤基因融合。转录共激活因子 VGLL2-NCOA2 在婴儿横纹肌肉瘤中的融合就是一个例子。为了描绘 VGLL2-NCOA2 的肿瘤发生机制并确定治疗弱点，我们采用了跨物种比较肿瘤学方法，包括斑马鱼、小鼠同种异体移植和患者样本。我们发现，VGLL2-NCOA2 足以产生间充质肿瘤，这些肿瘤表现出未成熟骨骼肌的特征，并重现了人类疾病。一部分 VGLL2-NCOA2 斑马鱼肿瘤在转录上与胚胎体节发生聚类，并确定了 VGLL2-NCOA2 的发育程序，包括 RAS 家族 GTP 酶 ARF6。在 VGLL2-NCOA2 斑马鱼、小鼠和患者肿瘤中，ARF6 高度表达。ARF6 基因敲除可抑制 VGLL2-NCOA2 在细胞培养中的致癌活性，更广泛地说，ARF6 在成人和儿科肉瘤中过度表达。我们的数据表明，VGLL2-NCOA2 是一种癌基因，它利用发育程序进行肿瘤发生，而 ARF6 的重新激活或持续存在可能代表治疗机会。
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