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

Abstract

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.

Characteristics and outcomes of gallbladder cancer patients at the Tata Medical Center, Kolkata 2017–2019

“…Potentially, the development of ex vivo organoid models of GBC may offer pre‐clinical models to evaluate both repurposing of drugs and identifying novel compounds. 39 , 40 …”

Application and Progress of Cultured Models of Gallbladder Carcinoma

“…Compared with the widespread application of GBC cell lines, the culture of primary GBC cells has also been further developed and applied. Bo et al 47 collected resected lesions from patients with gallbladder adenoma and GBC, and successfully cultured primary gallbladder tumor cells in vitro. To improve the efficiency of primary cell culture, Noggin, epidermal growth factor (EGF), fibroblast growth factor 10 (FGF10), and insulin-like growth factor (IGF) were added to the cell culture medium, and Wnt3a, Rspo1, and prostaglandin E2 were added to the gallbladder adenoma medium at the same time.…”

Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions

“…Organoids are defined as three-dimensional structures derived from primary cells that self-organise through cell-to-cell and cell-to-matrix interactions and recapitulate aspects of the native tissue architecture and function in vitro 148 149. Increasing evidence supported the feasibility of deriving cancer organoids from fresh tumour tissue to establish the so-called ‘minitumours’ that can be grown in plastic and contribute to the advancement in tumour biology and precision medicine 150. There is growing evidence demonstrating the feasibility of CCA organoids in either resectable151–153 or advanced disease 154.…”