Single-cell analysis reveals that GFAP+ dedifferentiated Schwann cells promote tumor progress in PNI-positive distal cholangiocarcinoma via lactate/HMGB1 axis

• DOI: 10.1038/s41419-025-07543-x
• Publication Date: 2025-03-27T23:08:38Z
• Authors: Ziyang Zu; Chong Zhang; Jianxiang Shi; Kunlun Chen; Hongwei Tang; Kaizhao Hu; Enchi Liu; Chengyang Ji; Ruo Feng; Xiaojing Shi; Wenlong Zhai
• Keywords: Perineural invasion

Abstract 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 dCCA. Deciphering the complex interplay between neoplastic neural cells crucial understanding mechanisms propelling PNI-positive dCCA progression. Herein, we conduct single-cell RNA sequencing on 24,715 from pairs tumors adjacent tissues, identifying eight unique cell types. Malignant exhibit significant inter- intra-tumor heterogeneity. We delineate compositional functional phenotypes five Schwann (SC) subsets in Moreover, our analyses reveal potential subtypes critical to forming PNI: NEAT1 + malignant characterized by hypoxic propensity GFAP dedifferentiated SCs featuring hypermetabolism. Further bioinformatics uncover extensive interactions these subpopulations. Functional experiments confirm lactate tumor microenvironment can induce GFAP-dedifferentiation SCs, which promotes cancer progression through upregulating HMGB1. Taken together, findings offer thorough characterization transcriptional profile unveil therapeutic targets PNI.