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Updated: Oct 25, 2025
A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
Published on: September 30, 2021
Multi-omics data integration reveals novel drug targets in hepatocellular carcinoma
Christos Dimitrakopoulos1,2,3, Sravanth Kumar Hindupur4,5, Marco Colombi4
1Department of Biosystems Science and Engineering, ETH Zürich, 4058, Basel, Switzerland.
Background:
Genetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood.
Results:
Here, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 'mediators' that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC.
Conclusions:
This study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.
Insights
This study identifies key molecular mediators linking genetic changes to hepatocellular carcinoma (HCC) development. Targeting these mediators, like YAP1 and GRB2, may offer new treatments for mTOR-driven HCC.
Area of Science:
- Oncology
- Molecular Biology
- Systems Biology
Background:
- Genetic aberrations are common in hepatocellular carcinoma (HCC), but their functional impact is not fully understood.
- Understanding these functional consequences is crucial for developing effective HCC therapies.
Purpose of the Study:
- To investigate the functional consequences of genetic alterations in hepatocellular carcinoma (HCC).
- To identify molecular mediators that link genetic changes to multi-omic alterations in HCC.
Main Methods:
- Utilized an mTOR-driven hepatocellular carcinoma mouse model.
- Employed Network-based Integration of multi-omic data (NetICS) to analyze transcriptome, proteome, and phosphoproteome data.
- Validated findings in human HCC samples.
Main Results:
- Identified 74 molecular mediators that transmit the effects of genetic and miRNA expression changes.
- These mediators explain the impact of oncogenic mTOR signaling on cellular processes.
- Confirmed dysregulation of YAP1, GRB2, SIRT1, HDAC4, and LIS1 in human HCC.
Conclusions:
- Targeting YAP1 or GRB2 signaling pathways could be a therapeutic strategy for HCC.
- Modulating pathways involved in global histone acetylation may benefit patients with mTOR-hyperactive HCC.
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