University Health Network, Ontario Cancer Institute/Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Clin Cancer Res. 2020 Mar 1;26(5):1162-1174. doi: 10.1158/1078-0432.CCR-19-1376. Epub 2019 Nov 6.
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.
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.
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.
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.
非小细胞肺癌（NSCLC）是全球癌症相关死亡的最常见原因。因此，人们迫切需要开发新的具有临床相关性的 NSCLC 模型，以加速药物靶点的确定和对该疾病的认识。
对 30 例手术切除的 NSCLC 原发性患者组织和 35 例先前建立的患者来源异种移植（PDX）模型进行了类器官培养建立的处理。通过细胞学和组织学、外显子组测序和 RNA 测序分析对类器官进行组织学和分子特征分析。通过将类器官皮下注射到 NOD/SCID 小鼠中来评估其致瘤性。通过 EGFR、FGFR 和 MEK 靶向治疗对类器官进行药物测试。
我们已经确定了有利于建立源自原发性肺患者和 PDX 肿瘤组织的 NSCLC 类器官的短期和长期扩增的细胞培养条件。NSCLC 类器官再现了患者和 PDX 肿瘤的组织学特征。它们还保留了致瘤性，这一点可以通过恶性细胞的细胞学特征、异种移植的形成、保留的突变、拷贝数异常和全外显子和 RNA 测序中类器官与匹配的亲本肿瘤组织之间的基因表达谱来证明。NSCLC 类器官模型还保留了匹配的亲本肿瘤对靶向治疗的敏感性，并且可以用于验证或发现生物标志物-药物组合。
我们的 NSCLC 类器官面板紧密再现了患者肿瘤的基因组学和生物学特征，是药物测试和生物标志物验证的潜在平台。
