National Chengdu Center for Safety Evaluation of Drugs and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610000, China.
Sichuan Kangcheng Biotechnology Co., Ltd. Chengdu 610000, China.
Cancer Biol Med. 2021 Feb 15;18(1):184-198. doi: 10.20892/j.issn.2095-3941.2020.0012.
Patient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but their consistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This study aimed to establish a PDX repository for non-small cell lung cancer (NSCLC) and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients.
A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice. Based on the successful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGFR, and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detected whole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES) analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin, doxorubicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents.
A large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients' tumor samples. WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX models responded differentially to the standard-of-care treatment, including chemo-, targeted- and immuno-therapeutics.
Our established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening, biomarker discovery, and translational research.
患者来源的异种移植（PDX）模型在临床前和转化应用中显示出巨大的潜力，但它们在表型、遗传和药效动力学异质性方面与原发性肿瘤的一致性尚未得到很好的研究。本研究旨在建立非小细胞肺癌（NSCLC）的 PDX 数据库，并进一步阐明其是否能够保留患者肿瘤内和肿瘤间的异质性。
共将 75 例手术切除的 NSCLC 标本植入免疫缺陷 NOD/SCID 小鼠体内。基于成功建立 NSCLC PDX 模型，我们通过苏木精和伊红染色和免疫组织化学染色比较了癌组织和 PDX 模型中波形蛋白、Ki67、EGFR 和 PD-L1 蛋白的表达。此外，我们还检测了原发肿瘤和 PDX 代之间的全基因表达谱。我们还对 17 个第一代异种移植物进行了全外显子组测序（WES）分析，以进一步评估 PDX 是否保留了患者的异质性。最后，使用紫杉醇、顺铂、多柔比星、阿特珠单抗、阿法替尼和 AZD4547 评估 PDX 模型对标准治疗药物的反应。
成功开发了大量可连续移植的 NSCLC PDX 模型。PDX 异种移植的组织学和病理免疫组织化学与患者的肿瘤样本一致。WES 和 RNA-seq 进一步证实 PDX 准确地复制了原发性肿瘤的分子异质性。与临床患者相似，PDX 模型对标准治疗药物（包括化疗、靶向治疗和免疫治疗）的反应存在差异。
我们建立的 NSCLC PDX 模型忠实地再现了分子、组织病理学和治疗特征，以及相应的肿瘤异质性，为药物筛选、生物标志物发现和转化研究提供了一个临床相关的平台。
