Dataset Information

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.

SUBMITTER: Yuan B

PROVIDER: S-EPMC8786696 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPatient-derived organoids (PDO) have been proposed as a novel in vitro method of drug screening for different types of cancer. However, to date, extrahepatic biliary tract carcinoma (eBTC) PDOs have not yet been fully established.MethodsWe collected six samples of gallbladder carcinoma (GBC) and one sample of extrahepatic cholangiocarcinoma (eCCA) from seven patients to attempt to establish eBTC PDOs for drug screening. We successfully established five GBC and one eCCA PDOs. Histological staining was used to compare structural features between the original tissues and cancer PDOs. Whole exome sequencing (WES) was performed to analyze the genetic profiles of original tissues and cancer PDOs. Drug screening, including gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, infigratinib, and ivosidenib, was measured and verified by clinical effects in certain cases.ResultsDifferent PDOs exhibited diverse growth rates during in vitro culture. Hematoxylin and eosin staining demonstrated that the structures of most cancer PDOs retained the original structures of adenocarcinoma. Immunohistological and periodic acid-schiff staining revealed that marker expression in cancer PDOs was similar to that of the original specimens. Genetic profiles from the four original specimens, as well as paired cancer PDOs, were analyzed using whole exome sequencing. Three of the four PDOs exhibited a high degree of similarity when compared to the original specimens, except for GBC2 PDO, which only had a concordance of 74% in the proportion of single nucleotide polymorphisms in the coding sequence. In general, gemcitabine was found to be the most efficient drug for eBTC treatment, as it showed moderate or significant inhibitory impact on cancer growth. Results from drug screening were confirmed to a certain extent by three clinical cases.ConclusionsOur study successfully established a series of eBTC PDOs, which contributed to the field of eBTC PDOs. Additional enhancements should be explored to improve the growth rate of PDOs and to preserve their immune microenvironment.