VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis.
VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis.
复制标题
DOI：
10.1016/j.celrep.2023.112013
复制
发表时间：
2023-01-31
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
临床测序工作正在快速识别缺乏功能验证的肉瘤基因融合。一个例子是在婴儿横纹肌肉瘤中发现的转录辅助激活因子VGLL2-NCOA2的融合。为了描述VGLL2-NCOA2的致瘤机制和确定治疗的脆弱性，我们对斑马鱼、小鼠同种异体移植和患者样本实施了跨物种比较肿瘤学方法。我们发现VGLL2-NCOA2足以产生表现出未成熟骨骼肌特征的间充质肿瘤，并概括了人类的疾病。VGLL2-NCOA2斑马鱼肿瘤的一个子集在转录上与胚胎体细胞发生聚集在一起，并鉴定了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高表达。ARF6基因敲除抑制细胞培养中VGLL2-NCOA2的致癌活性，更广泛地说，ARF6在成人和儿童肉瘤中过表达。我们的数据表明，VGLL2-NCOA2是一种癌基因，它利用肿瘤发生的发育程序，而ARF6的重新激活或持续可能代表着一种治疗机会。Watson等人。使用跨物种比较的方法来建立斑马鱼和小鼠的罕见的融合驱动的儿童肉瘤模型。这些模型概括了人类疾病，这些系统的整合确定了一个保守的发育靶点ARF6。ARF6与主要致癌驱动因素合作，代表了一个潜在的治疗机会。
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. Watson et al. use a cross-species comparative approach to develop zebrafish and mouse models of a rare fusion-driven pediatric sarcoma. These models recapitulate the human disease, and the integration of these systems identifies a conserved developmental target, ARF6. ARF6 cooperates with the primary oncogenic driver, representing a potential therapeutic opportunity.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1002/jbmr.4102
发表时间：
2020-10
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Chakraborty N;Waning DL;Gautam A;Hoke A;Sowe B;Youssef D;Butler S;Savaglio M;Childress PJ;Kumar R;Moyler C;Dimitrov G;Kacena MA;Hammamieh R
通讯作者：
Hammamieh R
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1097/pas.0000000000001140
发表时间：
2018-11
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Argani P;Reuter VE;Kapur P;Brown JE;Sung YS;Zhang L;Williamson R;Francis G;Sommerville S;Swanson D;Dickson BC;Antonescu CR
通讯作者：
Antonescu CR
影响因子：
46.9
作者：
Bray, Nicolas L.;Pimentel, Harold;Pachter, Lior
通讯作者：
Pachter, Lior