Hepatic Stem Cell-like Subtypes of Hepatocellular Carcinoma Revealed from the Integrative Multi-omics Analysis Using Developmental Hierarchies of the Liver

Abstract

Background: Hepatocellular carcinoma (HCC) is lethal malignancy showing high relapse rates after curative resection in early-stage. Aggressive tumor biology in resectable HCC remains unclear. Methods: Using human fetal liver signatures, multi-omics dataset 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 worst prognosis with early recurrence even in early-stage. The oncogenic pathways in terms of cell cycle, epithelial-mesenchymal transition, and TGF-beta pathway were highly upregulated in the HS subtype. Higher mutations of TP53, RB1 with PTEN deletion were significantly identified in the HS subtype. We also identified subtype-specific tissue and serum biomarkers. Predicted responders for immunotherapy were significantly lower in stem cell-like subtypes due to higher accumulation of TAM and MDSC. The HS subtype showed potential higher response to multi-tyrosine kinase inhibitors, especially sorafenib and lenvatinib. Conclusion: Stem cell-like HCC is not only associated with significantly higher relapse rate after curative resection but also with molecular biology for the aggressive subtype of HCC. We identified subtype-specific serum and tissue biomarkers for stem cell-like subtypes and precise therapeutic strategies for each subtype regarding immunotherapy and molecular-targeted treatment. Our findings may offer theoretical foundation of biomarker-based clinical trials for new therapeutic approaches to resectable early-stage HCC patients.