Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma

• Published in: Journal of translational medicine Vol. 22; no. 1; p. 422
• Main Authors: Zhong, Yan-Jie, Luo, Xi-Mei, Liu, Fei, He, Zhi-Qiang, Yang, Si-Qi, Ma, Wen-Jie, Wang, Jun-Ke, Dai, Yu-Shi, Zou, Rui-Qi, Hu, Ya-Fei, Lv, Tian-Run, Li, Fu-Yu, Hu, Hai-Jie
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03.05.2024; BioMed Central; BMC
• Subjects: Analysis; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Cancer-associated fibroblasts; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cell Communication; Cellular signal transduction; Cholangiocarcinoma - genetics; Cholangiocarcinoma - pathology; Dosage and administration; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Health aspects; Humans; Immunosuppressive agents; Intercellular communication; Intrahepatic cholangiocarcinoma; Prognosis; Single cell transcriptomic; Single-Cell Analysis; Transcriptome - genetics; Tumor Microenvironment - genetics; WGCNA; China; Cancer-associated fibroblasts; Prognosis; Single cell transcriptomic; WGCNA; Intercellular communication; Intrahepatic cholangiocarcinoma
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-024-05238-z

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.