Clinical and translational medicine · 2026
Integrative characterization of human hepatocellular carcinoma-derived organoids and their HBV-associated biology.
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Kim Seo-Hyeon, Choi Young Rok, Choi Eun Woo, Kim Se Hui, Oh Seung Cheol, Kim Jae Yoon, Hong Su Young, Hong Suk Kyun, Lee Kwang-Woong, Ku Ja-Lok
Аннотация
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies and is characterized by a high degree of heterogeneity. However, HCC treatment remains difficult, highlighting the need to better define molecular subgroups of HCC and understand their potential relationships with therapeutic response.
METHODS: In this study, we established 20 patient-derived organoids and 12 patient-derived cell lines from 20 individuals diagnosed with HCC. These models were comprehensively characterized using whole-exome sequencing, RNA sequencing, drug screening, and hepatitis B virus (HBV)-targeting PCR with a focus on HBV-related HCC.
RESULTS: Based on transcriptomic profiling, this study classified HCC into two molecular subtypes, aligning with previously reported classifications. Drug screening revealed that the greater enrichment of the PI3K/AKT/mTOR signalling pathway was associated with increased sensitivity to everolimus and lenvatinib. Integrated transcriptomic and drug-response analyses further identified candidate genes associated with lenvatinib response. In addition, polymerase chain reaction (PCR) analysis targeting the HBV surface, core, and X genes demonstrated noticeable discrepancies relative to the clinically reported HBV infection status. Notably, HBV DNA detection was associated with activation of the calcium signalling pathway and oxaliplatin response.
CONCLUSIONS: This study provides a valuable resource for investigating the biology and pharmacological characteristics of HCC, particularly in the context of molecular subtypes and HBV-associated mechanisms. Ultimately, these findings offer additional insights into HCC heterogeneity and drug response and may serve as a basis for further investigation of molecular determinants of therapeutic response.
METHODS: In this study, we established 20 patient-derived organoids and 12 patient-derived cell lines from 20 individuals diagnosed with HCC. These models were comprehensively characterized using whole-exome sequencing, RNA sequencing, drug screening, and hepatitis B virus (HBV)-targeting PCR with a focus on HBV-related HCC.
RESULTS: Based on transcriptomic profiling, this study classified HCC into two molecular subtypes, aligning with previously reported classifications. Drug screening revealed that the greater enrichment of the PI3K/AKT/mTOR signalling pathway was associated with increased sensitivity to everolimus and lenvatinib. Integrated transcriptomic and drug-response analyses further identified candidate genes associated with lenvatinib response. In addition, polymerase chain reaction (PCR) analysis targeting the HBV surface, core, and X genes demonstrated noticeable discrepancies relative to the clinically reported HBV infection status. Notably, HBV DNA detection was associated with activation of the calcium signalling pathway and oxaliplatin response.
CONCLUSIONS: This study provides a valuable resource for investigating the biology and pharmacological characteristics of HCC, particularly in the context of molecular subtypes and HBV-associated mechanisms. Ultimately, these findings offer additional insights into HCC heterogeneity and drug response and may serve as a basis for further investigation of molecular determinants of therapeutic response.