Background/Objectives:Lung cancer is a highly diverse disease, and reliable preclinical models that accurately reflect tumor characteristics are essential for studying lung cancer biology and testing new therapies. This study aimed to establish patient-derived tumor organoids (PDTOs) using small biopsy samples and surgical specimens to create a model system that preserves the genetic and histological features of the original tumors.Methods:PDTOs were generated from 163 lung cancer specimens, including 109 samples obtained using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or bronchoscopy, 52 surgical specimens, and 2 pleural fluid samples. The organoid establishment rate beyond passage three was assessed, and histological subtypes and genetic profiles were analyzed using immunohistochemical staining and targeted exome sequencing.Results:The overall PDTO establishment rate was 34.4% (56/163), and 44.6% (25/56) of these organoids retained the histological and genetic features of the parental tumors. Genetic analysis identified key mutations, including KRAS G12C, EGFR L858R, MET exon 14 skipping mutation, and ROS1 fusion. PDTOs successfully formed tumors in mice while maintaining the genetic characteristics of the original tumors. Co-culture of PDTOs with cancer-associated fibroblasts (CAFs) resulted in increased resistance to paclitaxel. In the co-culture model of PDTOs with immune cells, dose-dependent growth inhibition of PDTOs was observed in response to immune checkpoint inhibitors.Conclusions:PDTOs established from small biopsy and surgical specimens serve as a valuable model for studying lung cancer biology, tumor microenvironment interactions, and drug response. This model has the potential to improve personalized treatment strategies.
背景/目的：肺癌是一种高度异质性疾病，建立能够准确反映肿瘤特征的可靠临床前模型对于研究肺癌生物学特性及测试新疗法至关重要。本研究旨在利用小活检样本和手术标本建立患者来源肿瘤类器官（PDTOs），构建能够保留原始肿瘤遗传学和组织学特征的模型系统。 方法：从163例肺癌标本中成功构建PDTOs，包括109例经支气管超声引导下经支气管针吸活检（EBUS-TBNA）或支气管镜获取的样本、52例手术标本及2例胸腔积液样本。评估传代三次以上的类器官建成功率，并通过免疫组织化学染色和靶向外显子组测序分析组织学亚型及遗传学特征。 结果：总体PDTOs建成功率为34.4%（56/163），其中44.6%（25/56）的类器官保留了亲本肿瘤的组织学和遗传学特征。遗传学分析鉴定出KRAS G12C、EGFR L858R、MET外显子14跳跃突变及ROS1融合等关键突变。PDTOs在小鼠体内成功成瘤并保持原始肿瘤的遗传特征。与癌症相关成纤维细胞（CAFs）共培养后，PDTOs对紫杉醇的耐药性增强。在PDTOs与免疫细胞共培养模型中，观察到免疫检查点抑制剂对PDTOs产生剂量依赖性生长抑制作用。 结论：基于小活检和手术标本建立的PDTOs可作为研究肺癌生物学特性、肿瘤微环境相互作用及药物反应的重要模型，该模型具有优化个体化治疗策略的潜力。
Establishment of Human Lung Cancer Organoids Using Small Biopsy and Surgical Tissues
肿瘤(癌症)患者之家