Generation of multicellular tumor spheroids with micro-well array for anticancer drug combination screening based on a valuable biomarker of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. More than 30% of patients with diagnosed HCC have abnormally high expression of fibroblast growth factor receptor 4 (FGFR4). Currently, clinical trials for a variety of FGFR4-specific inhibitors have started. However, the effect of these inhibitors is not ideal, and it is necessary to find a drug combination to synergistically exert anti-tumor effects. We found strong correlations between FGFR4 and HCC clinicopathological characteristics in the present study. After grouping patients according to FGFR4 expression, the key gene signatures were inputted the drug-gene related databases, which predicted several potential drug candidates. More importantly, to achieve the reliable and high throughput drug cytotoxicity assessment, we developed an efficient and reproducible agarose hydrogel microwells to generate uniform-sized multicellular tumor spheroids, which provide better mimicry of conventional solid tumors that can precisely represent anticancer drug candidates’ effects. Using high content screening, we quickly evaluated the enhanced anti-tumor effects of these combinations. Finally, we demonstrated that Parthenolide is a potential drug that can significantly enhance the clinical efficacy of FGFR4 receptor inhibitors. In general, we offered a new therapeutic way for FGFR4 positive HCC patients.

Development of a prognostic model based on anoikis-related genes for predicting clinical prognosis and immunotherapy of hepatocellular carcinoma

“…Risk stratification of hepatocellular carcinoma, including risk stratification algorithms and biomarkers, could help improve the effectiveness of HCC treatment by better identifying at-risk individuals [ 49 ]. In addition, the combination of valuable hepatocellular carcinoma biomarkers after screening into an array has positive significance in clinical application [ 50 ]. Due to the heterogeneity of tumors and individuals, a large enough biomarker pool is needed.…”

Deciphering the underlying mechanism of liver diseases through utilization of multicellular hepatic spheroid models

“…For cancer research, MCTS models serve as a transition between in vivo tumor models and in vitro cultured cancer cells (33,34).…”

“…In addition, Wang Q. et al produced MCTSs of uniform size using agarose hydrogel microwells. They demonstrated that this platform is accurate, efficient, and reproducible for determining the efficacy of candidate drugs to treat cancer, and they used the platform to show that parthenolide may increase the efficacy of inhibitors that act on the FGFR4 receptor (34).…”