Midkine as a driver of age-related changes and increase in mammary tumorigenesis [scATAC-seq]

Aging is one of the pivotal risk factors for cancer, notably in breast cancer with diagnosis striking at the average age of 62. However, the intricate mechanisms underlying aging and breast cancer susceptibility remain unclear. In this study, we depicted a comprehensive single-cell landscape of gene expression (scRNA-seq) and chromatin accessibility (scATAC-seq) of mammary glands from different aged rats. Mechanically, we revealed midkine, a growth factor secreted by basal epithelial cells, which might mediates the age-related mammary changes, as a validation, we treated young rats with midkine for a month and performed the single-cell transcriptome analysis on those mammary glands. We found midkine could largely mediates the transcriptional shift and hyperproliferation of aged epithelial cell by activating PI3K/AKT-SREBF1 signaling. Furthermore, we find the aging-related accumulation of midkine could largely mediated aging-related changes of mammary gland and promoting the tumorigenesis of breast tumors proved using a well-established Nitroso-N-methylurea (NMU)-induced breast cancer rat model. Our finding identify a promising biomarker and intervention target for both mammary aging and tumorigenesis.衰老是癌症的关键风险因素之一，在乳腺癌中尤为显著，该病确诊的平均年龄为62岁。然而，衰老与乳腺癌易感性背后的复杂调控机制仍未明晰。本研究绘制了不同年龄大鼠乳腺组织的单细胞基因表达（scRNA-seq）与染色质开放性（scATAC-seq）全景图谱。机制层面，我们揭示了中期因子（midkine）——一种由基底上皮细胞分泌的生长因子——可能介导年龄相关的乳腺组织变化；为验证上述结论，我们将年轻大鼠用中期因子处理一月，并对其乳腺组织开展单细胞转录组分析。我们发现，中期因子可通过激活PI3K/AKT-SREBF1信号通路，在很大程度上介导衰老上皮细胞的转录组转变与过度增殖。此外，借助成熟的N-亚硝基-N-甲基脲（Nitroso-N-methylurea, NMU）诱导乳腺癌大鼠模型，我们证实：年龄相关的中期因子积累可广泛介导乳腺的衰老相关改变，并促进乳腺肿瘤的发生发展。本研究成果为乳腺衰老与肿瘤发生均提供了极具潜力的生物标志物与干预靶点。