[Preliminary application of patient-derived tumor organoids in biliary tract cancers: analysis of 38 cases]

Abstract

Objective: To explore genomic features associated with gemcitabine sensitivity, patient-derived organoid models of biliary tract cancer (BTC) were established and characterized. Methods: This is an experimental study conducted from January 2020 to December 2023. The tissue specimens of BTC were collected from patients who underwent surgical resection at the Department of Hepatobiliary and Pancreatic Surgery,the Second Affiliated Hospital of Zhejiang University School of Medicine between January 2020 and December 2023. The tumor organoids were cultured in vitro and histologically characterized. Drug sensitivity testing was performed using gemcitabine,cisplatin,paclitaxel,fluorouracil,and lenvatinib etc. to evaluate cell viability. The correlation between the drug sensitivity of organoids and clinical therapeutic response was analyzed. Results: Thirty-eight patient-derived organoids (PDO) models were successfully established from 43 biliary tract malignancy patients with complete follow-up data,including gallbladder cancer PDO 14 cases,distal bile duct cancer PDO 16 cases,intrahepatic cholagiocarcinoma PDO 8 cases,achieving an overall success rate of 8/14. Drug sensitivity testing (DST) was performed on the successfully generated PDO,with 35 models successfully completing DST experiments. The overall consistency rate between drug responses in PDOs and clinical survival outcomes in corresponding patients was 8/14. Transcriptomic analysis of gemcitabine-sensitive vs. gemcitabine-resistant PDO identified 71 differentially expressed genes in the resistant group,the significant up-regulate genes including GLDC,LINC01595,IL-27,ANGPTL3,CYP7A1,and AKR1C1;the significant down-regulate genes including P2RY2,LIPC,and ECHDC3. Conclusion: A biobank of patient-derived organoids of BTC has been established,which demonstrating its potential as preclinical models and tools for predicting chemotherapy responses for BTC patients.