Single-cell transcriptome analysis of macrophage subpopulations contributing to chemotherapy resistance in ovarian cancer.

ABSTRACT

BACKGROUND: Ovarian cancer, a fatal gynecological malignancy, is primarily managed through surgery and chemotherapy. However, a significant challenge arises as patients frequently experience relapse due to chemotherapy resistance. This study delves into the complex functions and underlying mechanisms of macrophages in chemotherapy resistance in ovarian cancer. METHOD: The single-cell transcriptome sequencing data of ovarian cancer with or without chemotherapy were analyzed. Then, corresponding cell types were identified, and macrophages were extracted from all cells. Following the standardized single-cell analysis using the Seurat package, 15 distinct macrophage clusters were found and differentially expressed genes among them were analyzed. Moreover, their association with chemotherapy resistance was explored through cell proportions and gene expression. RESULT: In the single-cell transcriptomic analysis of ovarian cancer tissues before and after chemotherapy, the cellular proportion of CXCL5+ macrophages, THBS1+ macrophages, and MMP9+ macrophages were significantly increased following chemotherapy. Further investigation revealed that these macrophage subpopulations upregulated the expression of multiple pro-tumorigenic angiogenic or invasive factors, in addition to CXCL5, THBS1, and MMP9, including CTSL, CXCL1, and CCL18. Finally, pathway enrichment analysis revealed the significant activation of signaling pathways, such as NOD-like receptor, MAPK, and TNF in these macrophage subpopulations, which provides direction for studying the mechanism of these subpopulations. CONCLUSION: CXCL5+, THBS1+, and MMP9+ macrophage subpopulations exhibit an increased cellular prevalence post-chemotherapy and pro-tumorigenic molecular expression profiles, suggesting a close association with chemoresistance in ovarian cancer. These findings contribute to our understanding of the roles and mechanisms of macrophages in ovarian cancer chemoresistance, providing a theoretical basis and direction for the development of therapies targeting macrophages in overcoming ovarian cancer chemoresistance.