2. Academic Validation
  3. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis

Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis

  • Nature. 2025 Jan;637(8044):184-194. doi: 10.1038/s41586-024-08285-0.
Xueqian Zhuang 1,  Qing Wang 2,  Simon Joost 1,  Alexander Ferrena 3,  David T Humphreys 2,  Zhuxuan Li 1 4,  Melissa Blum 1,  Klavdija Krause 1,  Selena Ding 1,  Yuna Landais 2,  Yingqian Zhan 5,  Yang Zhao 6,  Ronan Chaligne 7,  Joo-Hyeon Lee 8 9,  Sebastian E Carrasco 10,  Umeshkumar K Bhanot 11,  Richard P Koche 5,  Matthew J Bott 1,  Pekka Katajisto 12 13 14,  Yadira M Soto-Feliciano 15 16,  Thomas Pisanic 17,  Tiffany Thomas 18,  Deyou Zheng 3 19,  Emily S Wong 2 20,  Tuomas Tammela 21
Affiliations

Affiliations

  • 1 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
  • 3 Institute for Clinical and Translational Research, Albert Einstein College of Medicine, New York, NY, USA.
  • 4 Weill Cornell Graduate School of Medical Science, Weill Cornell Medicine, New York, NY, USA.
  • 5 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • 7 Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
  • 9 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • 10 Laboratory of Comparative Pathology, Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center and Rockefeller University, New York, NY, USA.
  • 11 Pathology Core Facility, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 12 Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
  • 13 Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
  • 14 Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
  • 15 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 16 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 17 Institute for NanoBioTechnology, Department of Oncology-Cancer Genetics and Epigenetics, Johns Hopkins University, Baltimore, MD, USA.
  • 18 Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
  • 19 Departments of Genetics, Neurology, and Neuroscience, Albert Einstein College of Medicine, New York, NY, USA.
  • 20 School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, New South Wales, Australia.
  • 21 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. tammelat@mskcc.org.
PMID: 39633048 DOI: 10.1038/s41586-024-08285-0
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.

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