What question did this study set out to answer?

The aim is to develop patient-derived liver cancer organoids to enhance diagnostics and personalize therapies.

March 18, 2026Open Access

Single-cell transcriptomic mapping of patient-derived primary liver cancer organoids reveals molecular subtypes and guides precision drug targeting

Key Points

The aim is to develop patient-derived liver cancer organoids to enhance diagnostics and personalize therapies.
Generated organoids from three liver cancer subtypes
Performed whole exome sequencing and RNA sequencing
Conducted drug screening targeting specific molecular pathways
Used single-cell RNA sequencing to map cell populations
Organoids maintained genetic fidelity to parental tumors
Distinct cell populations identified in different subtype organoids
Lipid metabolism was enriched in HCC, aiding growth inhibition with rosuvastatin
Tumor migration pathways were upregulated in ICC, targeted by pemigatinib
Mitochondrial function enhanced in CHC, impaired by regorafenib

Abstract

Current liver cancer research lacks reliable in vitro models that replicate tumor pathophysiology. This study establishes primary liver cancer (PLC) organoids from three major subtypes—hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (CHC)—to enable precise diagnostics and personalized therapies through comprehensive genomic profiling. Organoid cultures were generated from 11 PLC patients (5 HCC, 3 ICC, 3 CHC). Whole exome sequencing (WES), RNA-seq, and single-cell RNA-seq (scRNA-seq) were performed to analyze molecular differences. Drug screening targeting subtype-specific pathways was conducted to validate sequencing findings. WES and RNA-seq confirmed that organoids retained parental tumor genetics and heterogeneity, distinct from paracancerous tissues. scRNA-seq revealed distinct cell populations in HCC, ICC, and CHC organoids. Lipid metabolism was enriched in HCC organoids; tumor migration pathways were upregulated in ICC organoids; and mitochondrial function was enhanced in CHC organoids. Rosuvastatin inhibited HCC growth by targeting lipid metabolism, while pemigatinib reduced ICC malignancy by suppressing epithelial-mesenchymal transition. Regorafenib impaired mitochondrial function in CHC organoids, slowing progression. PLC-derived organoids serve as robust tools for biomarker discovery and drug screening. scRNA-seq elucidates inter- and intra-tumoral heterogeneity, offering insights for precision therapy in liver cancer. This model advances personalized treatment strategies for diverse PLC subtypes.

Bookmark

View Full Paper