Saltsman James A, Hammond William J, Narayan Nicole J C, Requena David, Gehart Helmuth, Lalazar Gadi, LaQuaglia Michael P, Clevers Hans, Simon Sanford
Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Pediatric Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Cancers (Basel). 2020 Sep 18;12(9):2668. doi: 10.3390/cancers12092668.
Hepatoblastoma is the most common childhood liver cancer. Although survival has improved significantly over the past few decades, there remains a group of children with aggressive disease who do not respond to current treatment regimens. There is a critical need for novel models to study aggressive hepatoblastoma as research to find new treatments is hampered by the small number of laboratory models of the disease. Organoids have emerged as robust models for many diseases, including cancer. We have generated and characterized a novel organoid model of aggressive hepatoblastoma directly from freshly resected patient tumors as a proof of concept for this approach. Hepatoblastoma tumor organoids recapitulate the key elements of patient tumors, including tumor architecture, mutational profile, gene expression patterns, and features of Wnt/β-catenin signaling that are hallmarks of hepatoblastoma pathophysiology. Tumor organoids were successfully used alongside non-tumor liver organoids from the same patient to perform a drug screen using twelve candidate compounds. One drug, JQ1, demonstrated increased destruction of liver organoids from hepatoblastoma tumor tissue relative to organoids from the adjacent non-tumor liver. Our findings suggest that hepatoblastoma organoids could be used for a variety of applications and have the potential to improve treatment options for the subset of hepatoblastoma patients who do not respond to existing treatments.
肝母细胞瘤是儿童期最常见的肝癌。尽管在过去几十年中生存率有了显著提高，但仍有一组患有侵袭性疾病的儿童对当前的治疗方案没有反应。由于该疾病的实验室模型数量较少，寻找新治疗方法的研究受到阻碍，因此迫切需要新的模型来研究侵袭性肝母细胞瘤。类器官已成为包括癌症在内的许多疾病的强大模型。我们已经从新鲜切除的患者肿瘤中直接生成并表征了一种侵袭性肝母细胞瘤的新型类器官模型，以此作为该方法的概念验证。肝母细胞瘤肿瘤类器官概括了患者肿瘤的关键要素，包括肿瘤结构、突变谱、基因表达模式以及Wnt/β-连环蛋白信号传导的特征，这些都是肝母细胞瘤病理生理学的标志。肿瘤类器官与来自同一患者的非肿瘤肝脏类器官一起成功用于使用12种候选化合物进行药物筛选。一种药物JQ1相对于来自相邻非肿瘤肝脏的类器官，显示出对肝母细胞瘤肿瘤组织的肝脏类器官的破坏增加。我们的研究结果表明，肝母细胞瘤类器官可用于多种应用，并且有可能改善对现有治疗无反应的肝母细胞瘤患者亚组的治疗选择。
