Fibronectin 1 derived from tumor-associated macrophages and fibroblasts promotes metastasis through the JUN pathway in hepatocellular carcinoma

Objective: Intercellular communication in the tumor microenvironment is a potential regulator of metastasis. To explore the specific mechanism, we performed a multi-omics analysis of hepatocellular carcinoma.Materials and methods: Multiple omics data including scRNA-seq, ATAC-seq, RNA-seq, and methylation data were obtained from GEO and TCGA databases. SCENIC was used to identify key transcription factors and their Reg-ulatory networks. ScMLnet was used to explore the mechanism of intercellular communication in the micro -environment. Multiple omics studies based on RNA-seq, ATAC-seq, and methylation data were used to explore downstream mechanisms of key transcription factors. Based on the analysis of cell differentiation trajectory and transcription subtypes, the regulation of cell communication on tumor subtypes was studied, and possible therapeutic compounds were explored. The universality of this mechanism was investigated by post-Pan-cancer analysis.Results: JUN and its regulatory network play a key role in HCC, which was mainly positively correlated with tumor-associated macrophages and fibroblasts. Intercellular communication analysis showed that macrophage and fibroblast-derived FN1 could increase JUN by TNFRSF11B/SMAD3. Multiomics analysis showed that KIF13A was a key downstream gene of JUN, which was involved in the activation of the hippo pathway. Analysis of cell differentiation trajectory, transcriptome subtypes, and neural network modeling showed that intercellular communication in the microenvironment can regulate the transcriptome characterization of HCC. Pan-cancer analysis indicates that this mechanism may be universal. Conclusion: FN1 derived from tumor-associated macrophages and fibroblasts promotes metastasis and alters transcriptome subtypes through the JUN-Hippo signaling pathway in HCC, which may be universal in cancers.

Automated summary

Through multi-omics analysis, this study found that intercellular communication in the tumor microenvironment can promote metastasis and alter transcriptome subtypes in hepatocellular carcinoma through the JUN-Hippo signaling pathway.