New Chondrosarcoma Cell Lines with Preserved Stem Cell Properties to Study the Genomic Drift During In Vitro/In Vivo Growth
New Chondrosarcoma Cell Lines with Preserved Stem Cell Properties to Study the Genomic Drift During In Vitro/In Vivo Growth
复制标题
DOI：
10.3390/jcm8040455
复制
发表时间：
2019-04-01
影响因子：
3.9
通讯作者：
Rodriguez, Rene
中科院分区：
文献类型：
--
作者：
Rey, Veronica;Menendez, Sofia T.;Rodriguez, Rene
在癌症基因组学时代，需要临床注释的接近患者的细胞系，适合研究改变的途径，并作为高通量药物筛选平台。这对于像软骨肉瘤这样的耐药肿瘤尤其重要，因为这种肿瘤几乎没有可用的模型。在这里，我们建立并鉴定了来自两个继发性（CDS06和CDS11）和一个去分化（CDS-17）软骨肉瘤的新细胞系，以及来自CDS-17生成的异种移植物（T-CDS17）的另一个细胞系。这些细胞系显示出癌症干细胞相关和侵袭性特征，并能够启动皮下和/或原位动物模型。在细胞系和肿瘤样本中检测到异柠檬酸脱氢酶-1 （IDH1）、异柠檬酸脱氢酶-2 （IDH2）和肿瘤抑制因子P53 （TP53）的不同突变和细胞周期蛋白依赖性激酶抑制剂2A （CDKN2A）的缺失。此外，在CDS17细胞培养过程中，出现了TP53的其他突变和小鼠双分钟2同源物（MDM2）的扩增。CDS17、T-CDS17和匹配患者样本的全外显子组测序分析证实，细胞系保留了肿瘤最相关的突变，发现了新的突变，并揭示了在体外/体内生长过程中出现的结构变异。总之，这项工作扩大了临床和遗传注释的软骨肉瘤系的范围，适用于体内研究和癌症干细胞（CSC）表征。此外，它还为软骨肉瘤细胞在适应生长条件过程中的遗传漂变提供了线索。
For the cancer genomics era, there is a need for clinically annotated close-to-patient cell lines suitable to investigate altered pathways and serve as high-throughput drug-screening platforms. This is particularly important for drug-resistant tumors like chondrosarcoma which has few models available. Here we established and characterized new cell lines derived from two secondary (CDS06 and CDS11) and one dedifferentiated (CDS-17) chondrosarcomas as well as another line derived from a CDS-17-generated xenograft (T-CDS17). These lines displayed cancer stem cell-related and invasive features and were able to initiate subcutaneous and/or orthotopic animal models. Different mutations in Isocitrate Dehydrogenase-1 (IDH1), Isocitrate Dehydrogenase-2 (IDH2), and Tumor Supressor P53 (TP53) and deletion of Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) were detected both in cell lines and tumor samples. In addition, other mutations in TP53 and the amplification of Mouse Double Minute 2 homolog (MDM2) arose during cell culture in CDS17 cells. Whole exome sequencing analysis of CDS17, T-CDS17, and matched patient samples confirmed that cell lines kept the most relevant mutations of the tumor, uncovered new mutations and revealed structural variants that emerged during in vitro/in vivo growth. Altogether, this work expanded the panel of clinically and genetically-annotated chondrosarcoma lines amenable for in vivo studies and cancer stem cell (CSC) characterization. Moreover, it provided clues of the genetic drift of chondrosarcoma cells during the adaptation to grow conditions.