Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis

Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, David T. Humphreys, Zhuxuan Li, Melissa Blum, Klavdija Krause, Selena Ding, Yuna Landais, Yingqian Zhan, Yang Zhao, Ronan Chaligne, Joo-Hyeon Lee, Sebastian E. Carrasco, Umeshkumar K. Bhanot, Richard P. Koche, Matthew J. Bott, Pekka Katajisto, Yadira M. Soto-Feliciano, Thomas Pisanic, Tiffany Thomas, Deyou Zheng, Emily S. Wong and Tuomas Tammela ()
Additional contact information
Xueqian Zhuang: Memorial Sloan Kettering Cancer Center
Qing Wang: Victor Chang Cardiac Research Institute
Simon Joost: Memorial Sloan Kettering Cancer Center
Alexander Ferrena: Albert Einstein College of Medicine
David T. Humphreys: Victor Chang Cardiac Research Institute
Zhuxuan Li: Memorial Sloan Kettering Cancer Center
Melissa Blum: Memorial Sloan Kettering Cancer Center
Klavdija Krause: Memorial Sloan Kettering Cancer Center
Selena Ding: Memorial Sloan Kettering Cancer Center
Yuna Landais: Victor Chang Cardiac Research Institute
Yingqian Zhan: Memorial Sloan Kettering Cancer Center
Yang Zhao: Johns Hopkins University
Ronan Chaligne: Memorial Sloan Kettering Cancer Center
Joo-Hyeon Lee: University of Cambridge
Sebastian E. Carrasco: Memorial Sloan Kettering Cancer Center and Rockefeller University
Umeshkumar K. Bhanot: Memorial Sloan Kettering Cancer Center
Richard P. Koche: Memorial Sloan Kettering Cancer Center
Matthew J. Bott: Memorial Sloan Kettering Cancer Center
Pekka Katajisto: University of Helsinki
Yadira M. Soto-Feliciano: Massachusetts Institute of Technology
Thomas Pisanic: Johns Hopkins University
Tiffany Thomas: Columbia University College of Physicians and Surgeons
Deyou Zheng: Albert Einstein College of Medicine
Emily S. Wong: Victor Chang Cardiac Research Institute
Tuomas Tammela: Memorial Sloan Kettering Cancer Center

Nature, 2025, vol. 637, issue 8044, 184-194

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-08285-0

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