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Peer-reviewedCC BY-NC-NDNature Cell Biology

Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution

  • Shiqi Diao1,2
  • Jia Yi Zou1,2
  • Shuo Wang2
  • Jason Earl Chan3,4
  • Roderik M. Kortlever5,6
  • Nicolas Poulain7
  • Nour Ghaddar2
  • Hyungdong Kim1,2
  • Gérard I. Evan5,6
  • Constantinos Koumenis8
  • Maria Hatzoglou9
  • Peter Walter10
4 more authors
  • Nahum Sonenberg11,12
  • John P. C. Le Quesne7,13,14
  • Tuomas Tammela3
  • Antonis E. Koromilas15,16,17
17 affiliations
  1. 1Graduate Program in Clinical and Translational Research, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
  2. 2Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada
  3. 3Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  4. 4Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  5. 5King's College London, London, UK
  6. 6The Francis Crick Institute, London, UK
  7. 7Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK
  8. 8Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
  9. 9Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
  10. 10Altos Laboratories, Bay Area Institute of Science, Redwood City, CA, USA
  11. 11Department of Biochemistry, McGill University, Montreal, Quebec, Canada
  12. 12Rosalind and Morris Goodman Cancer Institute, Montreal, Quebec, Canada
  13. 13Queen Elizabeth University Hospital, Greater Glasgow and Clyde NHS Trust, Glasgow, UK
  14. 14School of Cancer Sciences, University of Glasgow, Glasgow, UK
  15. 15Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. [email protected]
  16. 16Graduate Program in Clinical and Translational Research, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. [email protected]
  17. 17Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada. [email protected]
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Abstract

The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. The integrated stress response (ISR) is a key adaptive pathway that enables tumor survival under oncogenic stress. While ISR has been implicated in promoting tumor growth, its precise role in driving tumor evolution and heterogeneity has not been elucidated. In this study, using a genetically engineered mouse models, we demonstrate that ISR activation-indicated by elevated levels of phosphorylated eIF2 (p-eIF2) and ATF4-is essential for the emergence of dedifferentiated, therapy-resistant cell states. ISR, through the coordinated actions of ATF4 and MYC, facilitates the development of tumor cell populations characterized by high plasticity, stemness, and an epithelial-mesenchymal transition (EMT)-prone phenotype. This process is driven by ISR-mediated expression of genes that maintain mitochondrial integrity and function, critical for sustaining tumor progression. Importantly, genetic, or pharmacological inhibition of the p-eIF2-ATF4 signaling axis leads to mitochondrial dysfunction and significantly impairs tumor growth in mouse models of lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation is associated with poor prognosis and therapy resistance in advanced human LUAD, underscoring ISR inhibition as a promising therapeutic strategy to disrupt tumor evolution and counteract disease progression.

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Cite

BibTeXRIS
BibTeX
@article{diao2026integrated,
  title = {{Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution}},
  author = {Shiqi Diao and Jia Yi Zou and Shuo Wang and Jason Earl Chan and Roderik M. Kortlever and Nicolas Poulain and Nour Ghaddar and Hyungdong Kim and Gérard I. Evan and Constantinos Koumenis and Maria Hatzoglou and Peter Walter and Nahum Sonenberg and John P. C. Le Quesne and Tuomas Tammela and Antonis E. Koromilas},
  journal = {Nature Cell Biology},
  year = {2026},
  month = jun,
  doi = {10.1038/s41556-026-01991-z},
  url = {https://doi.org/10.1038/s41556-026-01991-z},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution
AU  - Shiqi Diao
AU  - Jia Yi Zou
AU  - Shuo Wang
AU  - Jason Earl Chan
AU  - Roderik M. Kortlever
AU  - Nicolas Poulain
AU  - Nour Ghaddar
AU  - Hyungdong Kim
AU  - Gérard I. Evan
AU  - Constantinos Koumenis
AU  - Maria Hatzoglou
AU  - Peter Walter
AU  - Nahum Sonenberg
AU  - John P. C. Le Quesne
AU  - Tuomas Tammela
AU  - Antonis E. Koromilas
PY  - 2026
DA  - 2026/06/15
JO  - Nature Cell Biology
DO  - 10.1038/s41556-026-01991-z
UR  - https://doi.org/10.1038/s41556-026-01991-z
AB  - The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. The integrated stress response (ISR) is a key adaptive pathway that enables tumor survival under oncogenic stress. While ISR has been implicated in promoting tumor growth, its precise role in driving tumor evolution and heterogeneity has not been elucidated. In this study, using a genetically engineered mouse models, we demonstrate that ISR activation-indicated by elevated levels of phosphorylated eIF2 (p-eIF2) and ATF4-is essential for the emergence of dedifferentiated, therapy-resistant cell states. ISR, through the coordinated actions of ATF4 and MYC, facilitates the development of tumor cell populations characterized by high plasticity, stemness, and an epithelial-mesenchymal transition (EMT)-prone phenotype. This process is driven by ISR-mediated expression of genes that maintain mitochondrial integrity and function, critical for sustaining tumor progression. Importantly, genetic, or pharmacological inhibition of the p-eIF2-ATF4 signaling axis leads to mitochondrial dysfunction and significantly impairs tumor growth in mouse models of lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation is associated with poor prognosis and therapy resistance in advanced human LUAD, underscoring ISR inhibition as a promising therapeutic strategy to disrupt tumor evolution and counteract disease progression.
SN  - 1465-7392
SN  - 1476-4679
ER  -