Ageing promotes metastasis via activation of the integrated stress response
Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood<sup>1</sup>. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.
Authors
- Samantha Alvarez
- Roger Olofsson Bagge (ORCID: https://orcid.org/0000-0001-5795-0355)
- Andreas Hallqvist (ORCID: https://orcid.org/0000-0002-3705-194X)
- Sama I. Sayin (ORCID: https://orcid.org/0000-0003-1993-3487)
- Anders Ståhlberg (ORCID: https://orcid.org/0000-0003-4243-0191)
- E. Bedel
- Jozef P. Bossowski
- Ahmed E. El Zowalaty (ORCID: https://orcid.org/0000-0001-6177-6142)
- Angana A. H. Patel (ORCID: https://orcid.org/0000-0001-5499-9655)
- Patrick Micke (ORCID: https://orcid.org/0000-0003-1210-5961)
- Kristell Le Gal (ORCID: https://orcid.org/0000-0002-5543-5082)
- Kevin X. Ali
- Levent M. Akyürek (ORCID: https://orcid.org/0000-0002-1968-6458)
- Jozefina J. Dzanan
- Emma Jonasson (ORCID: https://orcid.org/0000-0003-0463-9373)
- Davide Angeletti (ORCID: https://orcid.org/0000-0002-5256-1972)
- Thales Papagiannakopoulos (ORCID: https://orcid.org/0000-0002-2251-1624)
- Anetta Härtlová (ORCID: https://orcid.org/0000-0002-8152-4361)
- Dorota Raj (ORCID: https://orcid.org/0000-0002-7357-2902)
- Volkan I. Sayin (ORCID: https://orcid.org/0000-0002-5225-8260)
- Clotilde Wiel (ORCID: https://orcid.org/0000-0001-7042-4990)
- Ella Ä. Eklund (ORCID: https://orcid.org/0000-0002-7962-6836)
- Johan Botling (ORCID: https://orcid.org/0000-0003-2226-3517)
- Martin Dankis
- Heba Albatrok
- Maria Schwarz (ORCID: https://orcid.org/0000-0002-0405-6795)
- Nadia Gul
- Ray Pillai
- Ilayda Altinönder
Institutions
- Uppsala University (SE)
- University of Freiburg (DE)
- Sahlgrenska University Hospital (SE)
- Region Västra Götaland (SE)
- Institute for Biomedicine (IT)
- Wallenberg Wood Science Center (SE)
- Institute of Medical Microbiology and Hygiene (DE)
- New York University (US)
- Friedrich Schiller University Jena (DE)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature
- Published
- 2026-03-11
- DOI
- https://doi.org/10.1038/s41586-026-10216-0
- Primary Topic
- Endoplasmic Reticulum Stress and Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00