ScRNA-Seq Deciphers an Autocrine EFNA1-EPHA1 Loop That Reprograms the Microenvironment in Hepatocellular Carcinoma.

Area of Science:

• Single-cell analysis of intercellular communication in cancer biology.
• Molecular mechanisms of hepatocellular carcinoma (HCC) progression.
• Tumor microenvironment remodeling in liver cancer.

Background:

• Hepatocytes exhibit significant heterogeneity between normal and hepatocellular carcinoma (HCC) tissues.
• Malignant hepatocytes play a key role in remodeling the tumor microenvironment via ligand-receptor interactions.
• Mechanisms of hepatocyte-driven HCC progression at the single-cell level are poorly understood.

Purpose of the Study:

• To decode intercellular communication networks in HCC at the single-cell level.
• To identify key ligand-receptor interactions driving HCC progression.
• To investigate the role of hepatocyte signaling in reshaping the tumor microenvironment.

Main Methods:

• Analysis of single-cell RNA sequencing datasets (GSE174748, GSE166635) using CellChat.
• Validation of key findings via immunofluorescence in clinical HCC tissues and cell lines (HepG2/LO2).
• Assessment of clinical relevance using TCGA-LIHC dataset and UALCAN portal.

Main Results:

• HCC hepatocytes exhibit upregulated malignancy-related genes (AFP, ACSL4, SERPINA1) and act as signal senders/receivers.
• Enhanced EPHA signaling and the EFNA1-EPHA1 axis were identified as prominent ligand-receptor interactions in HCC.
• EFNA1 upregulation in HCC correlates with advanced stage, higher tumor grade, and metastasis, validated by TCGA analysis.

Conclusions:

• Malignant hepatocytes promote HCC progression via autocrine and paracrine signaling through the EFNA1-EPHA1 axis.
• The EFNA1-EPHA1 axis reshapes the tumor microenvironment in HCC.
• The EFNA1-EPHA1 axis represents a promising therapeutic target for HCC.