Chen Wei, Zhou Cheng, Liu Gao, Wang Xinyu, Yi Yong, Xu Yang, Qiu ShuangJian
Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China.
Department of Emergency Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Discov Oncol. 2025 Aug 26;16(1):1626. doi: 10.1007/s12672-025-03481-4.
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.
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.
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.
The findings suggest that PCK1 and ALDH1A1 may serve as potential biomarkers for predicting treatment response and guiding therapeutic strategies in HCC patients.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因，通常在晚期被诊断出来，治疗选择有限。尽管包括使用乐伐替尼在内的全身治疗取得了进展，但由于耐药性和肿瘤异质性，晚期HCC的生存率仍然很低。
本研究采用单细胞测序和空间转录组学来研究肿瘤内异质性，并识别具有固有耐药性的恶性细胞亚群。从接受乐伐替尼治疗的患者身上获取肿瘤样本，并进行差异分析以识别与耐药性相关的生物标志物。
分析显示，同一患者体内不同HCC结节之间的治疗反应存在显著差异，表明存在肿瘤内异质性。单细胞测序和空间转录组学确定了肿瘤内不同的细胞簇，其中特定亚群对乐伐替尼表现出固有抗性。差异分析确定了17个共同上调的基因，包括PCK1和ALDH1A1，它们与耐药性显著相关。伪时间分析进一步支持了PCK1和ALDH1A1作为HCC固有耐药性潜在生物标志物的作用。本研究强调了肿瘤异质性以及识别HCC中与耐药性相关生物标志物的重要性。
研究结果表明，PCK1和ALDH1A1可能作为预测HCC患者治疗反应和指导治疗策略的潜在生物标志物。
