Abstract
PURPOSE: Tuberous sclerosis complex (TSC) is a kind of rare genetic disorder caused by TSC1/TSC2 gene mutations and presented as angiomyolipoma (AML) in kidney. Previous studies have indicated the presence of estrogen-related heterogeneity in TSC, but this aspect has not been extensively explored. METHODS: In the present study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the estrogen-related heterogeneity in TSC-AML. A total of two female and two male TSC-AML patients were included in this study. RESULTS: Our results revealed the presence of various cell types within the TSC-AML tissue, including macrophages, endothelial cells, dendritic cells, neutrophils, B cells, fibroblasts, and tumor cells. Among the macrophage population, the immune-suppressive C1QC-Macro cells constituted the majority, and these cells were found to be more prevalent in female patients. AUCell analysis showed that estrogen-related pathways were significantly upregulated in C1QC-Macro cells in female patients compared to male patients. Furthermore, CellChat analysis demonstrated that tumor cells in female patients may regulate C1QC-Macro cells through the CXCL signaling pathway (CXCL12-CXCR4). In contrast, male patients exhibited enhanced interactions in stromal remodeling-related signaling pathways. Tumor cells were further categorized into TC1-TC6 subtypes. Notably, tumor cells with stem cell-like and EMT (epithelial-mesenchymal transition) characteristics were more common in male patients, whereas adipose-like, SMC-like, immune-suppressive, and fatty acid uptake-related tumor cells were more prevalent in female patients. Additionally, estrogen-related transcription factors (TFs), such as ESRRG, CREB1, CREB3L2, and CREB3L4, were activated in the stem cell-like tumor cells of female patients but not in those of male patients, suggesting that estrogen might play an important role in the pathogenesis of TSC-AML in females. CONCLUSION: Our findings indicate that estrogen regulates the formation of an immune-suppressive microenvironment and the development of stem cell-like tumors in female TSC-AML patients.