Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors
Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors
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DOI：
10.1002/ijc.30472
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发表时间：
2017-02-01
影响因子：
6.4
通讯作者：
Tsao, Ming-Sound
中科院分区：
文献类型：
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作者：
Wang, Dennis;Nhu-An Pham;Tsao, Ming-Sound
与人类肿瘤相似的肺癌模型的可用性仍然是癌症研究中的一个重大空白，因为肿瘤细胞系和小鼠模型可能无法概括患者中观察到的肺癌异质性谱。我们的目的是建立一个病人来源的肿瘤异种移植（PDX）的资源，从手术切除的非小细胞肺癌（NSCLC）。将来自手术切除的新鲜肿瘤组织植入非肥胖严重联合免疫缺陷（NOD SCID）γ小鼠的皮下袋中并使其生长。随后在NOD SCID小鼠中传代。通过全外显子组测序、单核苷酸多态性（SNP）和甲基化阵列以及通过质谱法的磷酸酪氨酸（pY）-蛋白质组来分析匹配的患者和PDX肿瘤以及非肿瘤性肺组织的子集。将这些数据与已发表的NSCLC原代和细胞系NSCLC数据集进行比较。从代表所有主要组织学亚型的441个肺癌中建立了127个稳定的PDX：52个腺癌、62个鳞状细胞癌、1个腺鳞癌、5个肉瘤样癌、5个大细胞神经内分泌癌和2个小细胞肺癌。36个PDX的体细胞突变、基因拷贝数和表达谱以及pY-蛋白质组图谱与患者肿瘤的相似性大于已建立的细胞系。癌症相关基因上的新体细胞突变被鉴定，但仅在PDX中，可能是由于PDX中的选择性克隆生长允许检测这些低等位基因频率突变。这些结果提供了迄今为止最有力的证据，证明从肺癌中建立的PDX与患者原发性肿瘤的特征非常相似。非小细胞肺癌（NSCLC）在组织学和遗传学上是多样的，只有一小部分患者表现出常见的癌症驱动突变。虽然将这种多样性转化为临床相关模型已被证明是困难的，但本研究表明，至少可以用患者源性肿瘤异种移植物（PDX）克服一些长期存在的挑战。通过将手术切除的人肿瘤组织植入小鼠并使其生长来建立PDX。随后的基因组和蛋白质组分析揭示了PDX与模型子集的匹配患者组织的分子病理学之间的保真度。与细胞系相比，PDXs更完整地再现了患者的肺癌发病机制。
Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice. Subsequent passages were in NOD SCID mice. A subset of matched patient and PDX tumors and non-neoplastic lung tissues were profiled by whole exome sequencing, single nucleotide polymorphism (SNP) and methylation arrays, and phosphotyrosine (pY)-proteome by mass spectrometry. The data were compared to published NSCLC datasets of NSCLC primary and cell lines. 127 stable PDXs were established from 441 lung carcinomas representing all major histological subtypes: 52 adenocarcinomas, 62 squamous cell carcinomas, one adeno-squamous carcinoma, five sarcomatoid carcinomas, five large cell neuroendocrine carcinomas, and two small cell lung cancers. Somatic mutations, gene copy number and expression profiles, and pY-proteome landscape of 36 PDXs showed greater similarity with patient tumors than with established cell lines. Novel somatic mutations on cancer associated genes were identified but only in PDXs, likely due to selective clonal growth in the PDXs that allows detection of these low allelic frequency mutations. The results provide the strongest evidence yet that PDXs established from lung cancers closely mimic the characteristics of patient primary tumors.What's new? Non-small cell lung cancers (NSCLCs) are histologically and genetically diverse, with only a small fraction of patients exhibiting common cancer-driving mutations. While translating that diversity into clinically relevant models has proven difficult, the present study suggests that at least some long-standing challenges may be overcome with patient-derived tumor xenografts (PDXs). PDXs were established by implanting and growing surgically resected human tumor tissue into mice. Subsequent genomic and proteomic profiling revealed fidelity between PDXs and the molecular pathology of matched patient tissues for a subset of models. Compared with cell lines, PDXs more completely recapitulated lung cancer pathogenesis in patients.