Single-cell RNA-seq integration unveils liver vulnerability to tumor metastases: insights from myeloid cell characterization in pancreatic cancer liver metastatic

Abstract

Abstract Background: The liver is the predominant metastatic site for diverse cancers, including pancreatic and colorectal cancers, etc. Liver metastasis increases cancer-related mortality, yet we have limited knowledge of the metastatic microenvironment to effectively target this process. Therefore, it is critical to understand the mechanisms underlying how the hepatic host tissues and immune cells differentially influence metastases in different cancers. Methods: We integrated two single-cell RNA-seq (scRNA-seq) datasets of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), including samples of primary pancreatic cancer (PP), primary colorectal cancer (PC), peripheral blood mono-nuclear cells (PBMC), adjacent normal pancreatic tissue (NPT), liver tissues from pancreatic cancer liver metastasis (P-LM), and colorectal cancer liver metastasis (C-LM). Cell clusters were manually annotated by known markers to demonstrate the cellular compositions of each group. We comparatively analyzed the cell-cell communications and enriched signaling pathways of P-LM and C-LM. The development trajectories of cell clusters were analyzed using Slingshot cell lineage inference algorithm. Results: In this study, we performed comparative analysis on cellular compositions between P-LM and C-LM and found myeloid cells exhibited a distinct enrichment profile between the two cancer metastases. Fifteen subclusters of 21,777 myeloid cells were recognized, including cell types such as macrophages, monocytes, and dendritic cells (DCs). We found Mph_SPP1, a subset of macrophages associated with angiogenesis and tumor invasion, was more prevalent in the P-LM group, indicating its specific pro-metastasis role in pancreatic cancers. Analysis of the developmental trajectory implied that Mph_SPP1 may progressively be furnished with increased expression of genes regulating endothelium as it evolved from monocytes. Cell-cell communications analysis revealed that Mph_SPP1 potentially interacts with endothelial cells in P-LM via FN1/SPP1-ITGAV/ITGB1, implying this macrophage subset may construct an immunosuppressive liver microenvironment for pancreatic cancer by regulating endothelial cells. We also found that Mph_SPP1 has a prognostic value in pancreatic adenocarcinoma that is not present in colon adenocarcinoma or rectum adenocarcinoma. Conclusions: We hypothesized that Mph_SPP1 actively creates a fertile environment for tumors when pancreatic cancer metastasizes to the liver and promote cancer invasion in a pro-angiogenetic pattern. Therefore, Mph_SPP1 has the potential to be a target of immunotherapy for liver metastasis in pancreatic cancer. These findings provide a foundation for understanding the immune characteristics of hepatic tumor microenvironment (TME) in patients with liver metastases and new ideas for the precise therapy of liver metastases.