Associate Professor CHA Bundang Medical Center / CHA University School of Medicine Seongnam, Kyonggi-do, Republic of Korea
Introduction: Hepatocellular carcinoma (HCC) is a lethal malignancy showing high relapse rates after curative resection in the early-stage. Genomic features of stem cell-like cancer cells contributing to aggressive tumor biology in HCC remain unclear. The aim of this study is to understand the underlying biology associated with HCC stemness to apply specific therapeutic strategies for resectable early-stage hepatocellular carcinoma.
Methods: Using human fetal liver signatures, Multi-omics datasets from multiple clinical HCC cohorts were analyzed comprehensively to reveal molecular mechanisms for HCC stemness as well as potential biomarkers to enhance therapeutic efficacy for molecular targeted therapy or immunotherapy in stem cell-like HCC subtypes.
Results: The patients predicted to the hepatic stem cell (HS) subtype showed aggressive tumor features, including large tumor size, high AFP, vascular invasion, and extrahepatic metastasis, as well as the worst prognosis with early recurrence even in early-stage. The oncogenic pathways in terms of the cell cycle, epithelial-mesenchymal transition, and TGF-beta pathway were highly upregulated in the HS subtype. Higher mutations of TP53, and RB1 with PTEN deletion were significantly identified in the HS subtype. We also demonstrated subtype-specific tissue biomarkers and serum biomarkers for the HS subtype. Predicted responders for immunotherapy were significantly lower in stem cell-like subtypes due to a higher accumulation of tumor-associated macrophages and myeloid-derived suppressor cells. The HS subtype showed potentially higher response to multi-tyrosine kinase inhibitors, especially sorafenib and lenvatinib.
Conclusion: Stem cell-like HCC is associated with a significantly higher relapse rate after curative resection and with molecular biology for the aggressive subtype of HCC. We identified subtype-specific serum and tissue biomarkers for the stem cell-like subtypes and precise therapeutic strategies for each subtype regarding immunotherapy and molecular-targeted treatment. Our findings may offer the theoretical foundation of biomarker-based clinical trials for new therapeutic approaches to resectable early-stage HCC patients.