Decoding the Mechanisms of Hepatocellular Carcinoma Cancer Stem Cells and Identifying Potential Therapeutic Strategies Based on Single-cell Omics

作者：Xiaotian Tan, Qiaoxian Luo, YING GE, NING DENG, PING JIN, MENGHUAN SONG, CAROLINA OI LAM UNG, Meiwan Chen, Hao Hu · 发表于：Cancer Genomics & Proteomics · 年份：2026 · DOI：10.21873/cgp.20577 · 被引用次数：1 · 研究领域：Cancer Cells and Metastasis、Single-cell and spatial transcriptomics、Liver physiology and pathology

BACKGROUND/AIM: Cancer stem cells (CSCs) play key roles in hepatocellular carcinoma (HCC) initiation, progression, therapeutic resistance, and recurrence, yet their cellular and spatial heterogeneity remains poorly understood. This study aimed to systematically characterize HCC-associated CSCs and identify prognostic biomarkers and potential therapeutic strategies using single-cell omics. MATERIALS AND METHODS: Single-cell RNA sequencing and spatial transcriptomics data were obtained from HCCDB v2.0. Malignant cells were re-clustered using Harmony-based batch correction, followed by uniform manifold approximation and projection (UMAP) and Louvain clustering. Copy number variation analysis validated malignant identities. CSC-associated molecular features were characterized using differential expression, gene regulatory network analysis (SCENIC), pathway enrichment (GSVA), pseudotime trajectory inference (Monocle, CytoTRACE2), and cell-cell communication analysis (CellChat). CSC-specific genes were integrated with GEO survival datasets (GSE76427, GSE14520) to construct a prognostic model, and potential CSC-targeting compounds were predicted using Connectivity Map. RESULTS: Six malignant subpopulations were identified, including a progenitor-like CSC subset expressing EPCAM, SOX9, and SOX4. Spatial transcriptomics revealed CSC enrichment at the tumor-stroma interface. CSCs exhibited strong stemness, metabolic plasticity, and invasive potential, with activation of WNT/β-catenin, ...