Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis Journal Article
| Authors: | Zhuang, X.; Wang, Q.; Joost, S.; Ferrena, A.; Humphreys, D. T.; Li, Z.; Blum, M.; Krause, K.; Ding, S.; Landais, Y.; Zhan, Y.; Zhao, Y.; Chaligne, R.; Lee, J. H.; Carrasco, S. E.; Bhanot, U. K.; Koche, R. P.; Bott, M. J.; Katajisto, P.; Soto-Feliciano, Y. M.; Pisanic, T.; Thomas, T.; Zheng, D.; Wong, E. S.; Tammela, T. |
| Article Title: | Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis |
| 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. © The Author(s), under exclusive licence to Springer Nature Limited 2024. |
| Keywords: | immunohistochemistry; adult; controlled study; human tissue; aged; middle aged; unclassified drug; human cell; methylation; histopathology; nonhuman; flow cytometry; cell proliferation; quality control; animal cell; mouse; phenotype; animal tissue; gene expression; animal experiment; animal model; genotype; lung cancer; transcription factor; immunofluorescence; dna methylation; histology; carcinogenesis; lung tumor; in situ hybridization; lung adenocarcinoma; dna; aging; real time polymerase chain reaction; tissue microarray; homeostasis; computer model; ex vivo study; lethargy; fluorescence activated cell sorting; dissociation; neutrophil gelatinase associated lipocalin; pyrosequencing; supplementation; inhibition; cell; lung injury; lung alveolus cell; hyperoxia; iron homeostasis; multiplicity of infection; fluorescence intensity; very elderly; cancer; human; article; differential gene expression; genetically engineered mouse strain; gene set enrichment analysis; crispr-cas9 system; deep neural network; humidity; plaque forming unit; suffocation; inductively coupled plasma mass spectrometry; cell stemness; transcription factor nupr1; hyperoxia lung injury; iron supplementation; lung dissociation |
| Journal Title: | Nature |
| Volume: | 637 |
| Issue: | 8044 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-02 |
| Start Page: | 184 |
| End Page: | 194 |
| Language: | English |
| DOI: | 10.1038/s41586-024-08285-0 |
| PUBMED: | 39633048 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Tuomas Tammela -- Erratum issued, see DOI: 10.1038/s41586-025-09124-6 -- Source: Scopus |
