Single-Cell Transcriptomic Analysis Reveals Macrophage–Tumor Crosstalk in Hepatocellular Carcinoma

Abstract

As one of the most malignant cancer, hepatocellular carcinoma (HCC) has a complex ecosystem featured by high heterogeneity. Cell crosstalk is demonstrated to be critical for HCC development. However, the cell communication orchestration in HCC remains largely unknown. Here, by analyzing the single-cell transcriptomes of the primary tumor tissues (n = 10) and tumor-adjacent tissues (n = 8) derived from 10 patients with HCC, we found that the proportions of plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells were reduced and that the proportion of macrophages was increased in the immune component of the primary tumor, compared with those in the tumor-adjacent tissue. Furthermore, we found widespread communication between macrophage populations and other cell types, and this communication was remarkably strengthened in the primary tumor, especially with HCC malignant cells. In addition, the SPP1–CD44 axis was identified as a unique interaction between macrophages and HCC malignant cells. Our comprehensive portrait of cell communication patterns over the HCC ecosystem reveals further insights into immune infiltration.

Multi-Transcriptomic Analysis Reveals the Heterogeneity and Tumor-Promoting Role of SPP1/CD44-Mediated Intratumoral Crosstalk in Gastric Cancer

“…Furthermore, these enhanced communications activated downstream target genes that were involved in cancer-related pathways, including the TGF-beta signaling pathway, MAPK signaling pathway, EMT-related pathways, and integrin cell surface interactions, leading to tumor progression and poor clinical GC outcomes. Liu et al showed that the SPP1-CD44 axis in hepatocellular carcinoma (HCC) leads to tumor progression, and that this axis could not be identified in the tumor-adjacent tissues of HCC, which is similar to the findings of our present study [45]. Recently, an in vitro study confirmed our findings regarding the role of the SPP1-CD44 axis in the tumorigenesis function of prostate cancer and found downstream pathways to promote tumor progression [46].…”

Systematic analysis and experimental validation of the prognostic and immunological effects of SPP1 tumor-associated macrophage features in colorectal cancer

“…Recent research has revealed malignant cells may act as a bridge between HCC malignant cells and macrophages, promoting macrophage transformation, in which SPP1-CD44 plays an important role. Similar results were found in pancreatic cancer and lung squamous cell carcinoma [32][33][34], and may also be suitable for colorectal cancer.…”

SPP1 is a prognostic related biomarker and correlated with tumor-infiltrating immune cells in ovarian cancer

“…Immune infiltrating cells in the tumor microenvironment (TME) have been shown to play a key role in tumor progression and influence clinical outcomes in cancer patients. Single-cell RNA sequencing (scRNA-seq) identified that SPP1-CD44 axis was a unique interaction between macrophages and HCC malignant cells, suggesting the role of macrophage-derived SPP1 in the progress of HCC [ 40 ]. Another single-cell and spatial analysis revealed interaction of FAP + fibroblasts and SPP1 + macrophages in colorectal cancer, and their presence is negatively correlated with lymphocyte infiltration and predicted a poor patient survival [ 41 ].…”