2. Academic Validation
  3. Ageing promotes metastasis via activation of the integrated stress response

Ageing promotes metastasis via activation of the integrated stress response

  • Nature. 2026 Apr;652(8112):1339-1348. doi: 10.1038/s41586-026-10216-0.
Angana A H Patel 1 2,  Jozefina J Dzanan # 1 2,  Kevin X Ali # 1 2,  Ella A Eklund # 1 2 3,  Samantha W Alvarez 1 2,  Dorota Raj 1 2,  Martin Dankis 1 2,  Ilayda Altinönder 1 2,  Maria Schwarz 1 2 4,  Kristell Le Gal 1 2,  Emre Bedel 1 2,  Ahmed Ezat El Zowalaty 1 2,  Emma Jonasson 5,  Heba Albatrok 5,  Nadia Gul 1 2,  Jozef P Bossowski 6 7,  Ray Pillai 6 7,  Patrick Micke 8,  Johan Botling 9,  Levent M Akyürek 9 10,  Davide Angeletti 11,  Sama I Sayin 1 2 3,  Anetta Härtlova 2 11 12,  Thales Papagiannakopoulos 6 7,  Roger Olofsson Bagge 1 2,  Anders Ståhlberg 2 5 13 14,  Andreas Hallqvist 3,  Clotilde Wiel 15 16,  Volkan I Sayin 17 18
Affiliations

Affiliations

  • 1 Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.
  • 2 Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
  • 3 Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
  • 4 Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany.
  • 5 Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
  • 6 Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
  • 7 Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
  • 8 Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
  • 9 Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
  • 10 Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
  • 11 Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy/Faculty of Science, University of Gothenburg, Gothenburg, Sweden.
  • 12 Institute of Medical Microbiology and Hygiene, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
  • 13 Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
  • 14 Science for Life Laboratory, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
  • 15 Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden. [email protected].
  • 16 Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. [email protected].
  • 17 Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden. [email protected].
  • 18 Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. [email protected].
  • # Contributed equally.
PMID: 41813904 DOI: 10.1038/s41586-026-10216-0
Abstract

Lung Cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. 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.

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