Gao Yun, Chen Xiaoyun, Zhu Yuerong, Zhou Suiqing, Zhang Long, Wu Qiuyue, Zhang Hui, Wang Ziyi, Chen Xuejiao, Xia Xinyi, Pu Liyong, Wang Xuehao
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
Hum Cell. 2024 Dec 6;38(1):27. doi: 10.1007/s13577-024-01148-w.
Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a unique subtype of primary liver cancer displaying both hepatocytic and cholangiocytic differentiation. The development of effective treatments for cHCC-CCA remains challenging because of its high heterogeneity and lack of a suitable model system. Using a three-dimensional culture system, we successfully established two novel cHCC-CCA organoid lines from patients undergoing surgical resection for primary liver cancer. cHCC-CCA organoid lines were authenticated by fingerprint analysis, and their morphology, growth kinetics, and anchorage-independent growth were also characterized. Hematoxylin and eosin staining and immunohistochemical analysis showed that the cHCC-CCA organoids preserved the growth pattern, differentiation grade, and phenotypic characteristics of their parental tumors. Whole-exome sequencing demonstrated that patient-derived cHCC-CCA organoid lines retained the genetic alterations identified in their original tumors. Subcutaneous tumors developed in immunodeficient mice after injection of cHCC-CCA organoids. Histologically, the xenografts recapitulated the features of the original cHCC-CCA tumors, harboring both HCC and intrahepatic cholangiocarcinoma components within the same tumor. The establishment of patient-derived cHCC-CCA organoid lines with high tumorigenicity provides a valuable resource for the mechanistic investigation and drug development of this disease.
肝内胆管癌合并肝细胞癌（cHCC-CCA）是原发性肝癌的一种独特亚型，兼具肝细胞和胆管细胞分化特征。由于其高度异质性且缺乏合适的模型系统，开发针对cHCC-CCA的有效治疗方法仍然具有挑战性。利用三维培养系统，我们成功地从接受原发性肝癌手术切除的患者中建立了两种新型的cHCC-CCA类器官系。通过指纹分析对cHCC-CCA类器官系进行了鉴定，并对其形态、生长动力学和非锚定依赖性生长进行了表征。苏木精和伊红染色以及免疫组化分析表明，cHCC-CCA类器官保留了其亲本肿瘤的生长模式、分化程度和表型特征。全外显子测序显示，患者来源的cHCC-CCA类器官系保留了其原始肿瘤中鉴定出的基因改变。将cHCC-CCA类器官注射到免疫缺陷小鼠体内后，可形成皮下肿瘤。组织学上，异种移植瘤重现了原始cHCC-CCA肿瘤的特征，在同一肿瘤内同时含有肝癌和肝内胆管癌成分。建立具有高致瘤性的患者来源的cHCC-CCA类器官系为该疾病的机制研究和药物开发提供了宝贵资源。
