Single-cell transcriptomic analysis identifies tissue-specific fibroblasts as the main modulators of myeloid cells in peritoneal metastasis of different origin

Abstract

Colorectal cancer (CRC) peritoneal metastasis (CPM) is related to limited therapy options and poor prognosis. Although stromal cells heavily infiltrate most CPMs, interactions between different cell types in their microenvironment remain unclear. Here, we investigated tumor and distant normal tissue from CPM and CRC patients using single-cell RNA sequencing. Investigating the incoming and outgoing signals between cells revealed that fibroblasts dominate the CPM signaling landscape with myeloid cells as their strongest interaction partner. Using immunohistochemistry, we confirmed that fibroblasts co-localize with macrophages in the CPM microenvironment. A fibroblast sub-population detected only in CPM and normal peritoneum demonstrated immunoregulatory properties in co-culture experiments, and was further detected in additional peritoneal malignancies derived from ovarian and gastric origin. This novel fibroblast type and its communication with macrophages could be attractive targets for therapeutic interventions in CPM and potentially peritoneal surface malignancies in general.

Keywords: Cancer-associated fibroblasts; Colorectal cancer; Peritoneal environment; Peritoneal metastasis; Tumor immunology.