Feng Xiaoqian, Huai Qian, Zhang Fumin, Yuan Wenkang, Li Xingyu, Yu Zhuo, Zhang Hao, Zhu Yaoling, Zhang Xu, Tao Baole, Dai Ying, Du Yishan
Department of Laboratory Medicine, the First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China.
Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
Cell Biosci. 2025 Jun 27;15(1):92. doi: 10.1186/s13578-025-01431-9.
Growth differentiation factors (GDFs) are a subfamily of the TGF-β superfamily whose expression increases in response to cellular stress and disease. Despite emerging cell- or animal-based evidence supporting an association between the GDF subfamily and cancer, systematic pan-cancer analyses of the GDF subfamily based on single-cell and spatial transcriptomes remains unavailable. In this study, we performed a comprehensive analysis of the GDF subfamily in 33 cancers, including expression, diagnosis, methylation, prognostic value, immune infiltration analysis, and potential biological pathways. We focused on the analysis of multi-group scRNA-seq and spatial data in hepatocellular carcinoma (HCC) to determine the role of the GDF family in the tumor microenvironment and its applicability in immunotherapy. Moreover, both the gain and loss of function strategies were used to assess the function of Growth differentiation factor 15 (GDF15) in cell lines of HCC. The GDF subfamily is expressed to varying degrees in most tumors and is significantly correlated with the prognosis of cancer patients. Subsequent scRNA-seq analysis depicted the heterogeneous cellular ecosystems of normal liver and HCC. Hepatocytes expressing GDF15 were less differentiated in HCC, and GDF15 promoted proliferation and invasion of HCC cell lines. Compared to normal liver, the strength of crosstalk between GDF15-positive Hepatocytes and other cells was enhanced in tumors, especially cancer-associated fibroblasts (CAFs)-derived Periostin and GDF15-positive Hepatocytes both regulate each other and jointly promote hepatocarcinogenesis. Further spatial transcriptomic data showed that GDF15 expression was negatively correlated with immune infiltration, especially in M1-type macrophages. Notably, validation analyses in bulk RNA-seq consistently emphasized the clinical significance of these findings. This study provides a comprehensive overview of the oncogenic role of the GDF subfamily in a wide range of tumors, highlights the important role of GDF15 in HCC ecosystem, and provides important biomarkers and potential therapeutic targets for future research.
生长分化因子（GDFs）是转化生长因子-β（TGF-β）超家族的一个亚家族，其表达会随着细胞应激和疾病而增加。尽管越来越多基于细胞或动物的证据支持GDF亚家族与癌症之间存在关联，但基于单细胞和空间转录组对GDF亚家族进行系统的泛癌分析仍然不可得。在本研究中，我们对33种癌症中的GDF亚家族进行了全面分析，包括表达、诊断、甲基化、预后价值、免疫浸润分析以及潜在的生物学途径。我们重点分析了肝细胞癌（HCC）中的多组单细胞RNA测序（scRNA-seq）和空间数据，以确定GDF家族在肿瘤微环境中的作用及其在免疫治疗中的适用性。此外，我们还采用了功能获得和功能丧失策略来评估生长分化因子15（GDF15）在HCC细胞系中的功能。GDF亚家族在大多数肿瘤中均有不同程度的表达，且与癌症患者的预后显著相关。随后的scRNA-seq分析描绘了正常肝脏和HCC的异质细胞生态系统。在HCC中，表达GDF15的肝细胞分化程度较低，且GDF15促进了HCC细胞系的增殖和侵袭。与正常肝脏相比，肿瘤中GDF15阳性肝细胞与其他细胞之间的串扰强度增强，尤其是癌症相关成纤维细胞（CAFs）来源的骨膜蛋白，且GDF15阳性肝细胞与CAFs相互调节并共同促进肝癌发生。进一步的空间转录组数据显示，GDF15表达与免疫浸润呈负相关，尤其是在M1型巨噬细胞中。值得注意的是，批量RNA测序中的验证分析始终强调了这些发现的临床意义。本研究全面概述了GDF亚家族在多种肿瘤中的致癌作用，突出了GDF15在HCC生态系统中的重要作用，并为未来研究提供了重要的生物标志物和潜在的治疗靶点。
