Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts

作者：De‐Zhen Guo, Xin Zhang, Sen-Quan Zhang, Shiyu Zhang, Xiangyu Zhang, Jiayan Yan, San-Yuan Dong, K. J. Zhu, Xin Yang, Fan Jia, Jian Zhou, Ao Huang · 发表于：Molecular Cancer · 年份：2024 · DOI：10.1186/s12943-024-02062-3 · 被引用次数：75 · 研究领域：Connective Tissue Growth Factor Research、Cancer Cells and Metastasis、Hippo pathway signaling and YAP/TAZ

Abstract Background Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear. Methods Integration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed. Results We established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1 + metabolism subtype (Metab-subtype), TOP2A + proliferation phenotype (Prol-phenotype), and S100A6 + pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-β signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop ...