Zu Ziyang, Zhang Chong, Shi Jianxiang, Chen Kunlun, Tang Hongwei, Hu Kaizhao, Liu Enchi, Ji Chengyang, Feng Ruo, Shi Xiaojing, Zhai Wenlong
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences & BGI College, Zhengzhou University, Zhengzhou, 450052, China.
Cell Death Dis. 2025 Mar 27;16(1):215. doi: 10.1038/s41419-025-07543-x.
Distal cholangiocarcinoma (dCCA) is a highly lethal malignancy that accounts for approximately 40% of patients with primary cholangiocarcinoma. Remarkable cellular heterogeneity and perineural invasion (PNI) are two typical features of dCCA. Deciphering the complex interplay between neoplastic and neural cells is crucial for understanding the mechanisms propelling PNI-positive dCCA progression. Herein, we conduct single-cell RNA sequencing on 24,715 cells from two pairs of PNI-positive dCCA tumors and adjacent tissues, identifying eight unique cell types. Malignant cells exhibit significant inter- and intra-tumor heterogeneity. We delineate the compositional and functional phenotypes of five Schwann cell (SC) subsets in PNI-positive dCCA. Moreover, our analyses reveal two potential cell subtypes critical to forming PNI: NEAT1 malignant cells characterized by hypoxic propensity and GFAP dedifferentiated SCs featuring hypermetabolism. Further bioinformatics uncover extensive cellular interactions between these two subpopulations. Functional experiments confirm that lactate in the hypoxic tumor microenvironment can induce GFAP-dedifferentiation in SCs, which promotes cancer cell invasion and progression through upregulating HMGB1. Taken together, our findings offer a thorough characterization of the transcriptional profile in PNI-positive dCCA and unveil potential therapeutic targets for dCCA PNI.
远端胆管癌（dCCA）是一种高度致命的恶性肿瘤，约占原发性胆管癌患者的40%。显著的细胞异质性和神经周围浸润（PNI）是dCCA的两个典型特征。阐明肿瘤细胞与神经细胞之间复杂的相互作用对于理解推动PNI阳性dCCA进展的机制至关重要。在此，我们对来自两对PNI阳性dCCA肿瘤及其相邻组织的24715个细胞进行了单细胞RNA测序，鉴定出八种独特的细胞类型。恶性细胞表现出显著的肿瘤间和肿瘤内异质性。我们描绘了PNI阳性dCCA中五个雪旺细胞（SC）亚群的组成和功能表型。此外，我们的分析揭示了对形成PNI至关重要的两种潜在细胞亚型：以低氧倾向为特征的NEAT1恶性细胞和以高代谢为特征的GFAP去分化SCs。进一步的生物信息学揭示了这两个亚群之间广泛的细胞相互作用。功能实验证实，低氧肿瘤微环境中的乳酸可诱导SCs中的GFAP去分化，通过上调HMGB1促进癌细胞侵袭和进展。综上所述，我们的研究结果全面表征了PNI阳性dCCA的转录谱，并揭示了dCCA PNI的潜在治疗靶点。
