Integrated characterization of hepatobiliary tumor organoids provides a potential landscape of pharmacogenomic interactions

Area of Science:

• Genomics
• Cancer Biology
• Drug Discovery

Background:

• Translating multiomics data into druggable targets for liver cancer remains a significant challenge.
• Identifying genomic alterations is crucial for developing effective liver cancer therapies.

Purpose of the Study:

• To establish and characterize patient-derived hepatobiliary tumor organoids (PDHOs) for liver cancer research.
• To integrate multiomics data with drug sensitivity profiles to uncover novel therapeutic strategies.
• To identify specific genomic alterations linked to drug responses in liver cancer.

Main Methods:

• Long-term culture of 64 patient-derived hepatobiliary tumor organoids (PDHOs) from a Chinese population.
• Comprehensive multiomics profiling including whole genome, transcriptome, and chromatin accessibility.
• Drug sensitivity screening against metabolism- and epigenetics-related chemicals and anti-cancer drugs.

Main Results:

• Observed divergent responses to 265 chemicals and 36 anti-cancer drugs across PDHOs.
• Defined over 32,000 genome-drug interactions by integrating multiomics and drug sensitivity data.
• Identified RUNX1 promoter mutation associated with increased chromatin accessibility, gene expression, and sensitivity to specific drugs.

Conclusions:

• The study provides an annotated PDHO biobank for human liver cancer research.
• A systematic approach for understanding liver cancer gene-regulatory networks and advancing personalized medicine was suggested.
• RUNX1 alterations represent a potential biomarker for targeted therapy selection in hepatobiliary tumors.