Challenges in Stratifying the Molecular Variability of Patient-Derived Colon Tumor Xenografts
Challenges in Stratifying the Molecular Variability of Patient-Derived Colon Tumor Xenografts
复制标题
DOI：
10.1155/2018/2954208
复制
发表时间：
2018-01-01
影响因子：
--
通讯作者：
Ostrowski, Jerzy
中科院分区：
文献类型：
--
作者：
Cybulska, Magdalena;Olesinski, Tomasz;Ostrowski, Jerzy
结直肠癌（CRC）是欧洲第二大常见癌症，也是全球主要死亡原因。患者来源的异种移植物（PDX）模型保持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小鼠中以建立异种移植模型。分别使用一组409个癌症相关基因和RNA-seq对原发性肿瘤和已建立的异种移植物进行组织学评估和遗传变异和基因表达调查。超过一半的CRC肿瘤（37例中的20例，54%）发展为PDX。组织学评估证实，PDX分级、基质成分、炎症和出芽与原发性肿瘤一致。DNA测序确定了每个样本每个基因平均0.14个变异。PDX中突变变体的百分比随着连续传代而增加，表明克隆异质性降低。对4180个差异表达的转录物的基因本体论分析（adj. p值< 0.05）揭示了在PDX中上调的转录物中参与细胞分裂和分解代谢过程的基因的过度表达;下调的转录物与细胞外基质组织、免疫应答和血管生成相关的GO术语相关。基于转录组的共有分子亚型（CMS）分类器和其他三个预测因子都不能可靠地将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之间的遗传和转录谱都不同，这可能是异种移植物发育早期亚克隆进化的结果，使得PDX的分子分层具有挑战性。
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.