A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12.
A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12.
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由脊索驱动的 HRASV12 表达启动的脊索瘤斑马鱼模型。
DOI：
10.1242/dmm.013128
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发表时间：
2014-07
影响因子：
4.3
通讯作者：
Haber DA
中科院分区：
文献类型：
--
作者：
Burger A;Vasilyev A;Tomar R;Selig MK;Nielsen GP;Peterson RT;Drummond IA;Haber DA
脊索瘤是一种恶性肿瘤，被认为起源于胚胎脊索的残余，起源于中轴骨骼的骨骼。手术切除是标准的治疗方法，通常与放射治疗相结合，但化疗和靶向治疗方法都没有取得成功。没有动物模型和只有少数脉络膜细胞系可用于临床前药物测试，并且，尽管没有鉴定出可药物化的遗传驱动因子，但已经描述了EGFR和下游AKT-PI 3 K通路的激活。在这里，我们报告了一个斑马鱼模型的脊索，基于稳定的转基因驱动的表达HRASV 12脊索细胞在发展过程中。广泛的脊索内肿瘤形成是明显的转基因表达的几天内，最终导致幼虫死亡。免疫组化和电子显微镜显示斑马鱼肿瘤具有人类脉络膜的特征。mTORC 1抑制剂雷帕霉素在脊索细胞系中具有一定的活性，可以延迟我们的斑马鱼模型中肿瘤形成的发生，并提高携带肿瘤的鱼类的存活率。因此，HRASV 12驱动的斑马鱼脊索瘤模型可以高通量筛选用于治疗这种难治性癌症的潜在治疗剂。
Chordoma is a malignant tumor thought to arise from remnants of the embryonic notochord, with its origin in the bones of the axial skeleton. Surgical resection is the standard treatment, usually in combination with radiation therapy, but neither chemotherapeutic nor targeted therapeutic approaches have demonstrated success. No animal model and only few chordoma cell lines are available for preclinical drug testing, and, although no druggable genetic drivers have been identified, activation of EGFR and downstream AKT-PI3K pathways have been described. Here, we report a zebrafish model of chordoma, based on stable transgene-driven expression of HRASV12 in notochord cells during development. Extensive intra-notochordal tumor formation is evident within days of transgene expression, ultimately leading to larval death. The zebrafish tumors share characteristics of human chordoma as demonstrated by immunohistochemistry and electron microscopy. The mTORC1 inhibitor rapamycin, which has some demonstrated activity in a chordoma cell line, delays the onset of tumor formation in our zebrafish model, and improves survival of tumor-bearing fish. Consequently, the HRASV12-driven zebrafish model of chordoma could enable high-throughput screening of potential therapeutic agents for the treatment of this refractory cancer.
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影响因子：
7.3
作者：
Presneau, Nadege;Shalaby, Asem;Flanagan, Adrienne M.
通讯作者：
Flanagan, Adrienne M.
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影响因子：
8.8
作者：
Hallor, K. H.;Staaf, J.;Jonsson, G.;Heidenblad, M.;von Steyern, F. Vult;Bauer, H. C. F.;IJszenga, M.;Hogendoorn, P. C. W.;Mandahl, N.;Szuhai, K.;Mertens, F.
通讯作者：
Mertens, F.
影响因子：
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作者：
Weinberger, PM;Yu, ZW;Sasaki, CT
通讯作者：
Sasaki, CT
影响因子：
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作者：
Dewaele B;Maggiani F;Floris G;Ampe M;Vanspauwen V;Wozniak A;Debiec-Rychter M;Sciot R
通讯作者：
Sciot R
影响因子：
--
作者：
Eisenberg, MB;Woloschak, M;Wolfe, D
通讯作者：
Wolfe, D