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
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
Nature. 2025 Jan;637(8044):184-194. doi: 10.1038/s41586-024-08285-0. Epub 2024 Dec 4.
Ageing is associated with a decline in the number and fitness of adult stem cells. Ageing-associated loss of stemness is posited to suppress tumorigenesis, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered mouse models and primary cells 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.
衰老与成体干细胞数量和功能的下降有关。衰老相关的干性丧失被认为会抑制肿瘤发生，但这一假设尚未在体内得到验证。在这里，我们使用生理衰老的原位基因工程小鼠模型和原代细胞来证明，衰老通过降解起源肺泡细胞的干性来抑制肺癌的起始和进展。这种表型的基础是在小鼠和人类的起源细胞中，衰老相关的转录因子NUPR1及其下游靶点lipocalin-2的诱导，这导致衰老细胞中功能性铁缺乏。NUPR1-lipocalin-2轴的基因失活或铁补充可挽救干性并促进衰老肺泡细胞的致瘤潜力。相反，靶向NUPR1-lipocalin-2轴通过诱导铁死亡对年轻肺泡细胞有害。特定增强子位点的衰老相关DNA低甲基化与NUPR1表达增加有关，这在年轻肺泡细胞中通过DNA甲基化抑制得以重现。我们发现，衰老导致功能性铁缺乏，进而导致干性丧失和肿瘤发生，但促进对铁死亡的抗性。这些发现对再生医学和癌症预防中细胞铁稳态的治疗调节具有启示意义。此外，我们的发现与一种模型一致，即大多数人类癌症在年轻时发生，从而突出了将癌症预防工作针对年轻人的重要性。
