Department of Genetics, Maria Sklodowska-Curie Institute-Oncology Centre, 02-781 Warsaw, Poland.
Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, 01-813 Warsaw, Poland.
Biomed Res Int. 2018 Dec 19;2018:2954208. doi: 10.1155/2018/2954208. eCollection 2018.
Colorectal cancer (CRC) is the second most common cancer in Europe and a leading cause of death worldwide. Patient-derived xenograft (PDX) models maintain complex intratumoral biology and heterogeneity and therefore remain the platform of choice for translational drug discovery. In this study, we implanted 37 primary CRC tumors and five CRC cell lines into NU/J mice to develop xenograft models. Primary tumors and established xenografts were histologically assessed and surveyed for genetic variants and gene expression using a panel of 409 cancer-related genes and RNA-seq, respectively. More than half of CRC tumors (20 out of 37, 54%) developed into a PDX. Histological assessment confirmed that PDX grading, stromal components, inflammation, and budding were consistent with those of the primary tumors. DNA sequencing identified an average of 0.14 variants per gene per sample. The percentage of mutated variants in PDXs increased with successive passages, indicating a decrease in clonal heterogeneity. Gene Ontology analyses of 4180 differentially expressed transcripts (adj. p value < 0.05) revealed overrepresentation of genes involved in cell division and catabolic processes among the transcripts upregulated in PDXs; downregulated transcripts were associated with GO terms related to extracellular matrix organization, immune responses, and angiogenesis. Neither a transcriptome-based consensus molecular subtype (CMS) classifier nor three other predictors reliably matched PDX molecular subtypes with those of the primary tumors. In sum, both genetic and transcriptomic profiles differed between donor tumors and PDXs, likely as a consequence of subclonal evolution at the early phase of xenograft development, making molecular stratification of PDXs challenging.
结直肠癌（CRC）是欧洲第二大常见癌症，也是全球主要的死亡原因。患者来源的异种移植（PDX）模型保留了复杂的肿瘤内生物学和异质性，因此仍然是转化药物发现的首选平台。在这项研究中，我们将 37 个原发性 CRC 肿瘤和 5 个 CRC 细胞系植入 NU/J 小鼠中，以开发异种移植模型。对原发性肿瘤和已建立的异种移植物进行组织学评估，并使用 409 个与癌症相关的基因和 RNA-seq 分别对遗传变异和基因表达进行调查。超过一半的 CRC 肿瘤（37 个中的 20 个，54%）发展为 PDX。组织学评估证实，PDX 分级、基质成分、炎症和芽生与原发性肿瘤一致。DNA 测序平均每个样本每个基因识别 0.14 个变异。PDX 中的突变变异百分比随着连续传代而增加，表明克隆异质性降低。对 4180 个差异表达转录本（adj. p 值 < 0.05）进行的基因本体论分析显示，在 PDX 中上调的转录本中，与细胞分裂和分解代谢过程相关的基因过度表达；下调的转录本与与细胞外基质组织、免疫反应和血管生成相关的 GO 术语相关。基于转录组的共识分子亚型（CMS）分类器或其他三个预测器都不能可靠地将 PDX 分子亚型与原发性肿瘤的分子亚型相匹配。总之，供体肿瘤和 PDX 之间的遗传和转录组谱存在差异，这可能是异种移植发展早期亚克隆进化的结果，使得 PDX 的分子分层具有挑战性。
