The Crosstalk Between Immune Infiltration, Circulating Tumor Cells, and Metastasis in Pancreatic Cancer: Identification of HMGB3 From a Multiple Omics Analysis

Hao-Dong Tang; Yang Wang; Peng Xie; Si-Yuan Tan; Hai-Feng Li; Hao Shen; Zheng Zhang; Zheng-Qing Lei; Jia-Hua Zhou

doi:10.3389/fgene.2022.892177

The Crosstalk Between Immune Infiltration, Circulating Tumor Cells, and Metastasis in Pancreatic Cancer: Identification of HMGB3 From a Multiple Omics Analysis

Front Genet. 2022 Jun 8:13:892177. doi: 10.3389/fgene.2022.892177. eCollection 2022.

Authors

Hao-Dong Tang¹, Yang Wang², Peng Xie¹, Si-Yuan Tan¹, Hai-Feng Li¹, Hao Shen¹, Zheng Zhang¹, Zheng-Qing Lei², Jia-Hua Zhou^{1

2}

Affiliations

¹ Department of Surgery, School of Medicine, Southeast University, Nanjing, China.
² Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China.

Abstract

Metastasis is the major cause of death in patients with pancreatic ductal adenocarcinoma (PDAC), and circulating tumor cells (CTCs) play an important role in the development of metastasis. However, few studies have uncovered the metastasis mechanism of PDAC based on CTCs. In this study, the existing bulk RNA-sequencing (bulk RNA-seq) and single-cell sequencing (scRNA-seq) data for CTCs in pancreatic cancer were obtained from the Gene Expression Omnibus (GEO) database. Analysis of tumor-infiltrating immune cells (TIICs) by CIBERSORT showed that the CTCs enriched from the peripheral blood of metastatic PDAC were found to contain a high proportion of T cell regulators (Tregs) and macrophages, while the proportion of dendritic cells (DCs) was lower than that enriched from localized PDAC. Through weighted gene co-expression network analysis (WGCNA) and the result of scRNA-seq, we identified the hub module (265 genes) and 87 marker genes, respectively, which were highly associated with metastasis. The results of functional enrichment analysis indicated that the two gene sets mentioned above are mainly involved in cell adhesion and cytoskeleton and epithelial-mesenchymal transition (EMT). Finally, we found that HMGB3 was the hub gene according to the Venn diagram. The expression of HMGB3 in PDAC was significantly higher than that in normal tissues (protein and mRNA levels). HMGB3 expression was significantly positively correlated with both EMT-related molecules and CTC cluster-related markers. Furthermore, it was also found that HMGB3 mutations were favorably related to tumor-associated immune cells through the TIMER2.0 online tool. We further demonstrated that PDAC patients with higher HMGB3 expression had significantly worse overall survival (OS) in multiple datasets. In summary, our study suggests that HMGB3 is a hub gene associated with EMT in CTCs, the formation of CTC clusters, and infiltration patterns of immune cells favorable for tumor progression and metastasis to distant organs.

Keywords: CIBERSORT; circulating tumor cells (CTCs); pancreatic ductal adenocarcinoma (PDAC); single-cell RNA-sequencing (scRNA-seq); weighted gene co-expression network analysis (WGCNA).