Single-cell profiles delineate immune cell remodeling and enhanced tumor-fibroblast interaction of hepatoblastoma after chemotherapy.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-10-01 DOI:10.1016/j.xcrm.2025.102401

Deqian Chen, Yong Zhan, Enqing Zhou, Huifen Chen, Shuyang Dai, Ran Yang, Chunjing Ye, Junfeng Wang, Yi Li, Yifei Lu, Ying Fang, Lian Chen, Wei Yao, Kai Li, Shan Zheng, Kuiran Dong, Jia Wang, Rui Dong

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引用次数: 0

Abstract

Hepatoblastoma (HB), the most common pediatric liver cancer, is typically treated with chemotherapy, yet its impact on the tumor microenvironment (TME) and mechanisms of chemoresistance remain unclear. We perform single-cell RNA sequencing (scRNA-seq) on 32 HB tumors pre- and post-chemotherapy, integrating data from spatial transcriptomics, bulk transcriptomics, multiplexed immunofluorescence, and patient-derived xenografts. Chemotherapy enriches CD69⁺CD8⁺ T cells and shifted myeloid cells toward immune-activating phenotypes. HB tumor cells exhibit both hepatic and mesenchymal features, with hepatic-like cells showing greater chemoresistance. A subset of AFP-high hepatic tumor cells expresses high fibroblast growth factor receptor 4 (FGFR4) and showed elevated proliferation. Post-treatment, mesenchymal-like tumor cells and MMP11⁺ cancer-associated fibroblasts enhance FGF-FGFR signaling. FGFR4 inhibition significantly suppressed tumor growth in xenografts. These findings provide a high-resolution landscape of the HB immune TME and highlight cancer-fibroblast interactions, especially via FGF signaling, as key contributors to chemoresistance.

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单细胞谱描绘了化疗后肝母细胞瘤免疫细胞重塑和增强的肿瘤-成纤维细胞相互作用。

肝母细胞瘤（HB）是最常见的儿科肝癌，通常采用化疗治疗，但其对肿瘤微环境（TME）的影响和化疗耐药机制尚不清楚。我们对32例化疗前后的HB肿瘤进行了单细胞RNA测序（scRNA-seq），整合了来自空间转录组学、大量转录组学、多路免疫荧光学和患者来源的异种移植物的数据。化疗使CD69+CD8+ T细胞富集，使骨髓细胞向免疫激活表型转移。HB肿瘤细胞表现出肝脏和间质特征，肝样细胞表现出更大的化疗耐药。高afp的肝肿瘤细胞亚群表达高成纤维细胞生长因子受体4 （FGFR4）并表现出高增殖。治疗后，间充质样肿瘤细胞和MMP11+癌症相关成纤维细胞增强了FGF-FGFR信号传导。FGFR4抑制显著抑制异种移植物的肿瘤生长。这些发现提供了HB免疫TME的高分辨率图像，并强调了癌症成纤维细胞相互作用，特别是通过FGF信号传导，是化疗耐药的关键因素。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.