VCAN is upregulated in the cervical cancer stroma and modulates macrophage polarization

The extracellular matrix (ECM) is a major component of the tumor microenvironment (TME) and plays an important role in cervical cancer progression. Versican, encoded by the VCAN gene, is a member of the aggrecan/proteoglycan family and has been reported as a marker of poor prognosis in cervical cancer. However, the versican-producing cells in cervical cancer tissue are not clearly identified. To identify the versican-producing cells in cervical cancer tissue, single-cell RNA sequencing (scRNA-seq) data of cervical cancer tissue are re-analyzed, and we find that versican is highly expressed in monocytes and fibroblasts. Immunohistochemical staining of cervical cancer and adjacent normal tissues showed that versican was predominantly expressed in non-parenchymal cells. Multiplex immunofluorescence staining further identified versican-expressing macrophages in cervical cancer tissues. We subsequently collected peripheral blood mononuclear cells (PBMCs) from a patient with cervical cancer before and after radiotherapy and performed scRNA-seq to investigate the highly variable genes in PBMCs. Notably, VCAN was identified as a monocyte-enriched gene and showed relatively high expression in the patient's circulating monocytes. We further investigated the effect of Versican core protein (VCAN-V3) on macrophages. The results suggest that VCAN-V3 predominantly suppresses M1-associated gene expression and induces a partial shift toward an M2-like transcriptional phenotype in RAW264.7 cells. In conclusion, our study demonstrates that stromal VCAN is upregulated in cervical cancer tissue. VCAN-V3 may influence the tumor microenvironment by modulating macrophage polarization-associated responses.