PDF(Pubmed)
Abstract：
Anaplastic thyroid cancer (ATC) is of the most aggressive thyroid cancer. While ATC is rare, it accounts for a disproportionately high number of thyroid cancer-related deaths. Here, we developed an ATC xenotransplant model in zebrafish larvae, where we can study tumorigenesis and therapeutic response in vivo. Using both mouse (T4888M) and human (C643)-derived fluorescently labeled ATC cell lines, we show these cell lines display different engraftment rates, mass volume, proliferation, cell death, angiogenic potential, and neutrophil and macrophage recruitment and infiltration. Next, using a PIP-FUCCI reporter to track proliferation in vivo, we observed cells in each phase of the cell cycle. Additionally, we performed long-term non-invasive intravital microscopy over 48 h to understand cellular dynamics in the tumor microenvironment at the single-cell level. Lastly, we tested two drug treatments, AZD2014 and a combination therapy of dabrafenib and trametinib, to show our model could be used as an effective screening platform for new therapeutic compounds for ATC. Altogether, we show that zebrafish xenotransplants make a great model to study thyroid carcinogenesis and the tumor microenvironment, while also being a suitable model to test new therapeutics in vivo.
摘要：
间变性甲状腺癌（ATC）是最具侵袭性的甲状腺癌。虽然ATC很少见，但它占甲状腺癌相关死亡人数的比例过高。在这里，我们在斑马鱼幼虫中开发了ATC异种移植模型，我们可以在体内研究肿瘤发生和治疗反应。使用小鼠（T4888M）和人（C643）衍生的荧光标记的ATC细胞系，我们显示这些细胞系显示不同的移植率，质量体积,扩散,细胞死亡,血管生成潜力和中性粒细胞和巨噬细胞募集和浸润。接下来,使用PIP-FUCCI报告基因跟踪体内增殖，我们观察到细胞处于细胞周期的每个阶段。此外,我们进行了超过48小时的长期非侵入性活体显微镜检查,以了解肿瘤微环境中单细胞水平的细胞动力学.最后,我们测试了两种药物治疗，AZD2014和dabrafenib和trametinib的联合治疗表明我们的模型可用作ATC新治疗化合物的有效筛选平台。总之,我们表明斑马鱼异种移植是研究甲状腺癌发生和肿瘤微环境的一个很好的模型，同时也是体内测试新疗法的合适模型。
