Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide, often diagnosed at advanced stages with limited treatment options. Despite advancements in systemic therapies, including the use of lenvatinib, the survival rate for advanced HCC remains low due to drug resistance and tumor heterogeneity. METHOD: This study employed single-cell sequencing and spatial transcriptomics to investigate intra-tumor heterogeneity and identify subpopulations of malignant cells with inherent drug resistance. Tumor samples were obtained from patients undergoing lenvatinib, and differential analysis was performed to identify biomarkers associated with drug resistance. RESULTS: Analysis revealed significant differences in treatment response between different HCC nodules within the same patient, indicating intra-tumor heterogeneity. Single-cell sequencing and spatial transcriptomics identified distinct cell clusters within tumors, with specific subpopulations showing inherent resistance to lenvatinib. Differential analysis identified 17 common upregulated genes, including PCK1 and ALDH1A1, which were significantly associated with drug resistance. Pseudotime analysis further supported the role of PCK1 and ALDH1A1 as potential biomarkers of inherent drug resistance in HCC. This study highlights the importance of tumor heterogeneity and identifying biomarkers associated with drug resistance in HCC. CONCLUSIONS: The findings suggest that PCK1 and ALDH1A1 may serve as potential biomarkers for predicting treatment response and guiding therapeutic strategies in HCC patients.