Single-cell RNA sequencing reveals the potential role of estrogen in tuberous sclerosis complex related renal angiomyolipoma

Yi Liu; Wenda Wang; Guoyang Zheng; Weifeng Xu; Zhan Wang; Xu Wang; Jiang Liu; Dongxu Qiu; Yanan Li; Yang Zhao; Yushi Zhang

doi:10.1007/s12672-025-02909-1

Single-cell RNA sequencing reveals the potential role of estrogen in tuberous sclerosis complex related renal angiomyolipoma

Discov Oncol. 2025 Jul 3;16(1):1255. doi: 10.1007/s12672-025-02909-1.

Authors

Yi Liu^#¹, Wenda Wang^#¹, Guoyang Zheng^#¹, Weifeng Xu¹, Zhan Wang¹, Xu Wang¹, Jiang Liu¹, Dongxu Qiu¹, Yanan Li¹, Yang Zhao², Yushi Zhang³

Affiliations

¹ Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. zhaoyangkypumch@163.com.
³ Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. beijingzhangyushi@126.com.

^# Contributed equally.

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.

Abstract

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