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

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Title: Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
Authors: Diao S; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.; Graduate Program in Clinical and Translational Research, Faculty of Medicine, McGill University, Montreal, Quebec, Canada., Zou JY; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.; Graduate Program in Clinical and Translational Research, Faculty of Medicine, McGill University, Montreal, Quebec, Canada., Wang S; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada., Chan JE; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Kortlever RM; The Francis Crick Institute, London, UK.; King's College London, London, UK., Poulain N; Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK., Ghaddar N; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada., Kim H; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.; Graduate Program in Clinical and Translational Research, Faculty of Medicine, McGill University, Montreal, Quebec, Canada., Evan GI; The Francis Crick Institute, London, UK.; King's College London, London, UK., Koumenis C; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Hatzoglou M; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA., Walter P; Altos Laboratories, Bay Area Institute of Science, Redwood City, CA, USA., Sonenberg N; Department of Biochemistry, McGill University, Montreal, Quebec, Canada.; Rosalind and Morris Goodman Cancer Institute, Montreal, Quebec, Canada., Le Quesne J; Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK.; School of Cancer Sciences, University of Glasgow, Glasgow, UK.; Queen Elizabeth University Hospital, Greater Glasgow and Clyde NHS Trust, Glasgow, UK., Tammela T; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Koromilas AE; Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada. antonis.koromilas@mcgill.ca.; Graduate Program in Clinical and Translational Research, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. antonis.koromilas@mcgill.ca.; Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada. antonis.koromilas@mcgill.ca.
Source: Nature cell biology [Nat Cell Biol] 2026 Jul; Vol. 28 (7), pp. 1529-1544. Date of Electronic Publication: 2026 Jun 15.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Macmillan Magazines Ltd Country of Publication: England NLM ID: 100890575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4679 (Electronic) Linking ISSN: 14657392 NLM ISO Abbreviation: Nat Cell Biol Subsets: MEDLINE
Imprint Name(s): Original Publication: London : Macmillan Magazines Ltd., [1999-
MeSH Terms: Mitochondria*/metabolism , Mitochondria*/pathology , Mitochondria*/genetics , Lung Neoplasms*/pathology , Lung Neoplasms*/genetics , Lung Neoplasms*/metabolism , Adenocarcinoma*/pathology , Adenocarcinoma*/genetics , Adenocarcinoma*/metabolism , Integrated Stress Response* , Cell Lineage* , Cellular Reprogramming*, Activating Transcription Factor 4/metabolism ; Activating Transcription Factor 4/genetics ; Adenocarcinoma of Lung/pathology ; Adenocarcinoma of Lung/genetics ; Adenocarcinoma of Lung/metabolism ; Eukaryotic Initiation Factor-2/metabolism ; Eukaryotic Initiation Factor-2/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Animals ; Humans ; Epithelial-Mesenchymal Transition ; Mice ; Cell Line, Tumor ; Metabolic Reprogramming ; Gene Expression Regulation, Neoplastic ; Phosphorylation ; Signal Transduction ; Cell Dedifferentiation ; Thyroid Nuclear Factor 1
Abstract: Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.
(© 2026. The Author(s).)
Competing Interests: Competing interests: The authors declare no competing interests.
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Grant Information: DK060569 U.S. Department of Health & Human Services | National Institutes of Health (NIH); PJT-168864 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); C4750/A12077 Cancer Research UK (CRUK); R01-CA268597 U.S. Department of Health & Human Services | National Institutes of Health (NIH); R01 CA268597 United States CA NCI NIH HHS; R01-CA270116 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); PJT-178173 Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
Substance Nomenclature: 145891-90-3 (Activating Transcription Factor 4)
0 (Nkx2-1 protein, mouse)
0 (Eukaryotic Initiation Factor-2)
0 (Proto-Oncogene Proteins c-myc)
0 (Transcription Factors)
0 (Atf4 protein, mouse)
0 (ATF4 protein, human)
0 (Thyroid Nuclear Factor 1)
Entry Date(s): Date Created: 20260615 Date Completed: 20260714 Latest Revision: 20260726
Update Code: 20260726
PubMed Central ID: PMC13364725
DOI: 10.1038/s41556-026-01991-z
PMID: 42298057
Database: MEDLINE
Description
ISSN:1476-4679
DOI:10.1038/s41556-026-01991-z