NR4A3high mast cells promote ovarian cancer metastasis by reprogramming tumor-associated macrophages via JAK2/STAT6 signaling

Tumor-associated mast cells in the tumor microenvironment play a critical and complex role in the progression of tumor malignancy. However, the key molecules that control mast cell activation and target the biological function of ovarian cancer (OC) cells are still not fully understood. In this study, we performed scRNA-seq on cells isolated from six cases of epithelial OC tissues (three cases of primary tumor and three of metastatic tumor), and we identified three mast cell subtypes, among which the proportion of the second group of mast cell subsets specifically expressing NR4A3 was significantly higher in the metastatic tissue than in the primary tissue, suggesting that NR4A3 expression of MC may be related to the metastasis and prognosis of OC. In vitro, the biological functions of constructed NR4A3^high bone-marrow-derived mast cells, such as degranulation response, showed a significant decline, but their secretion of high levels of CXCL16 and IL-8 promoted the polarization of macrophages to M2 through the STAT6 pathway, thus promoting the migration and invasion of OC. In ovarian tumor models in mice with mast cell deficiency (c-Kit W-sh/ W-sh), adoptive transfer of NR4A3^high mast cells can not only promote subcutaneous tumor growth, but also promote intraperitoneal tumor cell colonization, decrease the ratio of CD8+ T cells, and increase the ratio of M2 macrophages. These results indicate that NR4A3 can drive mast cells to release more CXCL16 and IL-8 and induce macrophage M2 polarization through STAT6 signaling pathway, thereby mediating the metastasis of ovarian cancer.