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Organoid Cultures as Preclinical Models of Non-Small Cell Lung Cancer.
文献信息
| DOI | 10.1158/1078-0432.CCR-19-1376 |
|---|---|
| PMID | 31694835 |
| 期刊 | Clinical cancer research : an official journal of the American Association for Cancer Research |
| 影响因子 | 10.2 |
| JCR 分区 | Q1 |
| 发表年份 | 2020 |
| 被引次数 | 172 |
| 关键词 | 类器官培养, 非小细胞肺癌, 药物测试, 生物标志物验证 |
| 文献类型 | Journal Article, Research Support, Non-U.S. Gov't |
| ISSN | 1078-0432 |
| 页码 | 1162-1174 |
| 期号 | 26(5) |
| 作者 | Ruoshi Shi, Nikolina Radulovich, Christine Ng, Ni Liu, Hirotsugu Notsuda, Michael Cabanero, Sebastiao N Martins-Filho, Vibha Raghavan, Quan Li, Arvind Singh Mer, Joshua C Rosen, Ming Li, Yu-Hui Wang, Laura Tamblyn, Nhu-An Pham, Benjamin Haibe-Kains, Geoffrey Liu, Nadeem Moghal, Ming-Sound Tsao |
一句话小结
本研究建立了一种非小细胞肺癌（NSCLC）类器官模型，能够再现患者肿瘤的组织学特征和基因组特征，并保持对靶向治疗的敏感性。这一模型为加速NSCLC的药物靶点识别和生物标志物验证提供了新的临床相关平台，具有重要的研究意义。
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类器官培养 · 非小细胞肺癌 · 药物测试 · 生物标志物验证
摘要
目的
非小细胞肺癌（NSCLC）是全球癌症相关死亡的最常见原因。迫切需要开发新的临床相关NSCLC模型，以加速药物靶点的识别和对该疾病的理解。
实验设计
对30例外科切除的NSCLC原发患者组织和35例之前建立的患者衍生异种移植（PDX）模型进行了处理，以建立类器官培养。通过细胞学和组织学、外显子组测序以及RNA测序分析对类器官进行了组织学和分子特征的表征。通过在NOD/SCID小鼠中皮下注射类器官来评估其肿瘤形成能力。类器官还接受了EGFR、FGFR和MEK靶向治疗的药物测试。
结果
我们已经确定了有利于从原发肺癌患者和PDX肿瘤组织中建立短期和长期扩展NSCLC类器官的细胞培养条件。NSCLC类器官重现了患者和PDX肿瘤的组织学特征。同时，它们保持了肿瘤形成能力，表现为恶性细胞特征、异种移植的形成、突变的保存、拷贝数异常以及通过全外显子组和RNA测序分析获得的类器官与匹配的原发肿瘤组织之间的基因表达谱等证据。NSCLC类器官模型还保留了匹配原发肿瘤对靶向治疗的敏感性，并可用于验证或发现生物标志物-药物组合。
结论
我们的NSCLC类器官面板与患者肿瘤的基因组学和生物学密切相符，可能成为药物测试和生物标志物验证的平台。
英文摘要
PURPOSE Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide. There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease.
EXPERIMENTAL DESIGN Thirty surgically resected NSCLC primary patient tissue and 35 previously established patient-derived xenograft (PDX) models were processed for organoid culture establishment. Organoids were histologically and molecularly characterized by cytology and histology, exome sequencing, and RNA-sequencing analysis. Tumorigenicity was assessed through subcutaneous injection of organoids in NOD/SCID mice. Organoids were subjected to drug testing using EGFR, FGFR, and MEK-targeted therapies.
RESULTS We have identified cell culture conditions favoring the establishment of short-term and long-term expansion of NSCLC organoids derived from primary lung patient and PDX tumor tissue. The NSCLC organoids recapitulated the histology of the patient and PDX tumor. They also retained tumorigenicity, as evidenced by cytologic features of malignancy, xenograft formation, preservation of mutations, copy number aberrations, and gene expression profiles between the organoid and matched parental tumor tissue by whole-exome and RNA sequencing. NSCLC organoid models also preserved the sensitivity of the matched parental tumor to targeted therapeutics, and could be used to validate or discover biomarker-drug combinations.
CONCLUSIONS Our panel of NSCLC organoids closely recapitulates the genomics and biology of patient tumors, and is a potential platform for drug testing and biomarker validation.
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主要研究问题
- 在NSCLC类器官培养中，如何优化培养条件以提高其生长和扩展的效率？
- 类器官模型在药物筛选中相比传统模型有哪些优势和局限性？
- 如何评估类器官模型对不同靶向治疗的敏感性，以便于个性化治疗的实施？
- 在建立NSCLC类器官时，如何确保其基因组特征与原发肿瘤的一致性？
- 类器官模型在发现新的生物标志物和药物组合方面，能提供哪些新的研究方向？
核心洞察
1. 研究背景和目的
非小细胞肺癌（NSCLC）是全球癌症相关死亡的主要原因之一，当前亟需开发新的临床相关模型，以加速新药靶点的识别和对疾病机制的理解。本研究旨在建立以患者来源的肿瘤组织为基础的类器官培养模型，以便更好地模拟NSCLC的生物学特性和药物反应，为未来的药物开发和生物标志物验证提供工具。
2. 主要方法和发现
研究团队从30例手术切除的NSCLC原发患者组织和35个已建立的患者来源异种移植（PDX）模型中提取样本，建立了类器官培养。通过细胞学和组织学、全外显子组测序以及RNA测序对类器官进行分子和组织学特征的表征。通过将类器官注射到NOD/SCID小鼠体内，评估其肿瘤形成能力。研究发现，NSCLC类器官能够在特定的培养条件下实现短期和长期扩展，并且成功地模拟了患者和PDX肿瘤的组织学特征，保留了肿瘤的恶性细胞学特征、基因突变、拷贝数变异及基因表达谱。此外，类器官对靶向治疗（如EGFR、FGFR和MEK抑制剂）的敏感性也得以保留。
3. 核心结论
本研究所建立的NSCLC类器官模型与患者肿瘤的基因组和生物学特征高度吻合，展示了其作为药物测试和生物标志物验证的平台的潜力。这些类器官不仅能够再现原始肿瘤的组织结构和生物学行为，还能够用于评估与肿瘤相关的药物反应，为个性化治疗提供了新的研究基础。
4. 研究意义和影响
本研究为NSCLC的研究和治疗提供了重要的实验模型，具有显著的临床应用潜力。通过使用类器官技术，研究人员能够更深入地理解肿瘤生物学，探索新药物的疗效，以及识别潜在的生物标志物，进而推动精准医学的发展。这一成果不仅有助于肿瘤基础研究，还可能加速新疗法的开发，提高NSCLC患者的治疗效果和生存率。
引用本文的文献
- Organoid of ovarian cancer: genomic analysis and drug screening. - H-D Liu;B-R Xia;M-Z Jin;G Lou - Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (2020)
- Conditional reprogramming: Modeling urological cancer and translation to clinics. - Wei Liu;Lingao Ju;Songtao Cheng;Gang Wang;Kaiyu Qian;Xuefeng Liu;Yu Xiao;Xinghuan Wang - Clinical and translational medicine (2020)
- Genomic characteristics and drug screening among organoids derived from non-small cell lung cancer patients. - Jing-Hua Chen;Xiang-Peng Chu;Jia-Tao Zhang;Qiang Nie;Wen-Fang Tang;Jian Su;Hong-Hong Yan;Hong-Ping Zheng;Ze-Xin Chen;Xin Chen;Meng-Meng Song;Xin Yi;Pan-Song Li;Yan-Fang Guan;Gang Li;Chu-Xia Deng;Rafael Rosell;Yi-Long Wu;Wen-Zhao Zhong - Thoracic cancer (2020)
- [Application of Organoids in Lung Cancer Precision Medicine]. - Ziqi Jia;Naixin Liang;Shanqing Li - Zhongguo fei ai za zhi = Chinese journal of lung cancer (2020)
- Human Lung Adenocarcinoma-Derived Organoid Models for Drug Screening. - Zhichao Li;Youhui Qian;Wujiao Li;Lisa Liu;Lei Yu;Xia Liu;Guodong Wu;Youyu Wang;Weibin Luo;Fuyuan Fang;Yuchen Liu;Fei Song;Zhiming Cai;Wei Chen;Weiren Huang - iScience (2020)
- Drug screening model meets cancer organoid technology. - Chen Liu;Tianyu Qin;Yuhan Huang;Yuan Li;Gang Chen;Chaoyang Sun - Translational oncology (2020)
- Engineered tissues and strategies to overcome challenges in drug development. - Andrew S Khalil;Rudolf Jaenisch;David J Mooney - Advanced drug delivery reviews (2020)
- Patient-derived cell line, xenograft and organoid models in lung cancer therapy. - Ku-Geng Huo;Elisa D'Arcangelo;Ming-Sound Tsao - Translational lung cancer research (2020)
- Lung organoids: advances in generation and 3D-visualization. - Brian Cunniff;Joseph E Druso;Jos L van der Velden - Histochemistry and cell biology (2021)
- Future perspectives from lung cancer pre-clinical models: new treatments are coming? - Francesca Bersani;Deborah Morena;Francesca Picca;Alessandro Morotti;Fabrizio Tabbò;Paolo Bironzo;Luisella Righi;Riccardo Taulli - Translational lung cancer research (2020)
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