Patient‐derived organoids for personalized gallbladder cancer modelling and drug screening

• Published in: Clinical and translational medicine Vol. 12; no. 1; pp. e678 - n/a
• Main Authors: Yuan, Bo, Zhao, Xiaofang, Wang, Xiang, Liu, Erdong, Liu, Chunliang, Zong, Yali, Jiang, Youhai, Hou, Minghui, Chen, Yao, Chen, Lei, Zhang, Yongjie, Wang, Hongyang, Fu, Jing
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2022; John Wiley and Sons Inc; Wiley
• Subjects: Adult; Aged; Aged, 80 and over; Cancer therapies; Clinical medicine; drug screening; Drug Screening Assays, Antitumor - methods; Drug Screening Assays, Antitumor - statistics & numerical data; Early Detection of Cancer - instrumentation; Early Detection of Cancer - methods; Early Detection of Cancer - statistics & numerical data; Exome Sequencing - methods; Exome Sequencing - statistics & numerical data; Female; Gallbladder; Gallbladder cancer; Gallbladder Neoplasms - diagnosis; Gallbladder Neoplasms - therapy; Gallstones; Gene expression; HDAC; Histology; Humans; Male; Middle Aged; Models, Biological; Mutation; organoids; Organoids - pathology; Patients; Precision Medicine - instrumentation; Precision Medicine - methods; Precision Medicine - statistics & numerical data; Surgery; United States > US; China; Germany; gallbladder cancer; drug screening; organoids; HDAC
• DOI: 10.1002/ctm2.678
• ISSN: 2001-1326

Background Gallbladder carcinoma (GBC) is a relatively rare but highly aggressive cancer with late clinical detection and a poor prognosis. However, the lack of models with features consistent with human gallbladder tumours has hindered progress in pathogenic mechanisms and therapies. Methods We established organoid lines derived from human GBC as well as normal gallbladder and benign gallbladder adenoma (GBA) tissues. The histopathology signatures of organoid cultures were identified by H&E staining, immunohistochemistry and immunofluorescence. The genetic and transcriptional features of organoids were analysed by whole‐exome sequencing and RNA sequencing. A set of compounds targeting the most active signalling pathways in GBCs were screened for their ability to suppress GBC organoids. The antitumour effects of candidate compounds, CUDC‐101 and CUDC‐907, were evaluated in vitro and in vivo. Results The established organoids were cultured stably for more than 6 months and closely recapitulated the histopathology, genetic and transcriptional features, and intratumour heterogeneity of the primary tissues at the single‐cell level. Notably, expression profiling analysis of the organoids revealed a set of genes that varied across the three subtypes and thus may participate in the malignant progression of gallbladder diseases. More importantly, we found that the dual PI3K/HDAC inhibitor CUDC‐907 significantly restrained the growth of various GBC organoids with minimal toxicity to normal gallbladder organoids. Conclusions Patient‐derived organoids are potentially a useful platform to explore molecular pathogenesis of gallbladder tumours and discover personalized drugs. We successfully established organoid lines derived from human GBC that recapitulated the histopathology, genetic and transcriptional features of the primary tissues. In drug screening experiment, we found that the dual PI3K/HDAC inhibitor CUDC‐907 significantly restrained the growth of various GBC organoids with minimal toxicity to normal gallbladder organoids.