美国斯隆凯特琳学院Tuomas Tammela课题组发现，衰老通过重新编程铁稳态限制干性和肿瘤发生。该项研究成果于2024年12月4日在线发表在《自然》杂志上。

研究人员使用生理性衰老的自发性基因工程小鼠模型和原代细胞，证明了衰老通过降低肺癌起源的肺泡细胞干性，抑制肺癌的启动和进展。该表型的基础是衰老引起转录因子NUPR1及其下游靶基因脂蛋白-2（lipocalin-2）在小鼠和人类的细胞中诱导，这导致衰老细胞的功能性铁缺乏。

遗传性去活化NUPR1–lipocalin-2轴或铁补充可以恢复干性并促进衰老肺泡细胞的肿瘤潜力。相反，靶向NUPR1–lipocalin-2轴通过诱导铁死亡对年轻肺泡细胞有害。衰老相关的特定增强子位点的DNA低甲基化与NUPR1表达增加相关，这一现象通过DNA甲基化抑制在年轻肺泡细胞中得到重现。

该研究揭示了衰老驱动功能性铁不足，导致干性丧失和肿瘤发生，但促进对铁死亡的耐受性。这些发现对再生医学和癌症预防中细胞铁稳态的治疗调控具有重要意义。此外，这些研究结果与一个模型一致，即大多数人类癌症在年轻时开始，这突显了将癌症预防努力集中于年轻人群的重要性。

研究人员表示，衰老与成人干细胞数量和活力的下降相关。衰老引起的干性丧失被认为抑制肿瘤发生，但这一假设尚未在体内进行验证。

附：英文原文

Title: Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis

Author: Zhuang, Xueqian, Wang, Qing, Joost, Simon, Ferrena, Alexander, Humphreys, David T., Li, Zhuxuan, Blum, Melissa, Krause, Klavdija, Ding, Selena, Landais, Yuna, Zhan, Yingqian, Zhao, Yang, Chaligne, Ronan, Lee, Joo-Hyeon, Carrasco, Sebastian E., Bhanot, Umeshkumar K., Koche, Richard P., Bott, Matthew J., Katajisto, Pekka, Soto-Feliciano, Yadira M., Pisanic, Thomas, Thomas, Tiffany, Zheng, Deyou, Wong, Emily S., Tammela, Tuomas

Issue&Volume: 2024-12-04

Abstract: Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1–lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1–lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.

DOI: 10.1038/s41586-024-08285-0

Source: https://www.nature.com/articles/s41586-024-08285-0