{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Graduate Program in Clinical and Translational Research, Faculty of Medicine, McGill University, Montreal, Quebec, Canada",
    "Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada",
    "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",
    "King's College London, London, UK",
    "The Francis Crick Institute, London, UK",
    "Cancer Research UK Scotland Institute, Garscube Estate, Glasgow, UK",
    "Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA",
    "Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA",
    "Altos Laboratories, Bay Area Institute of Science, Redwood City, CA, USA",
    "Department of Biochemistry, McGill University, Montreal, Quebec, Canada",
    "Rosalind and Morris Goodman Cancer Institute, Montreal, Quebec, Canada",
    "Queen Elizabeth University Hospital, Greater Glasgow and Clyde NHS Trust, Glasgow, UK",
    "School of Cancer Sciences, University of Glasgow, Glasgow, UK",
    "Gerald Bronfman Department of Oncology, Faculty of Medicine, McGill University, 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",
    "Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada. antonis.koromilas@mcgill.ca"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Shiqi Diao",
      "orcid": "0009-0005-9759-4638"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jia Yi Zou",
      "orcid": "0009-0006-9979-9300"
    },
    {
      "affs": [
        1
      ],
      "name": "Shuo Wang",
      "orcid": "0000-0001-7462-6178"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Jason Earl Chan",
      "orcid": "0000-0003-0552-8544"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Roderik M. Kortlever",
      "orcid": "0000-0001-5558-2851"
    },
    {
      "affs": [
        6
      ],
      "name": "Nicolas Poulain"
    },
    {
      "affs": [
        1
      ],
      "name": "Nour Ghaddar"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Hyungdong Kim",
      "orcid": "0000-0002-8003-2189"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Gérard I. Evan",
      "orcid": "0000-0003-0412-1216"
    },
    {
      "affs": [
        7
      ],
      "name": "Constantinos Koumenis",
      "orcid": "0000-0001-5945-4726"
    },
    {
      "affs": [
        8
      ],
      "name": "Maria Hatzoglou",
      "orcid": "0000-0003-2037-1231"
    },
    {
      "affs": [
        9
      ],
      "name": "Peter Walter",
      "orcid": "0000-0002-6849-708X"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Nahum Sonenberg",
      "orcid": "0000-0002-4707-8759"
    },
    {
      "affs": [
        6,
        12,
        13
      ],
      "name": "John P. C. Le Quesne",
      "orcid": "0000-0003-3552-7446"
    },
    {
      "affs": [
        2
      ],
      "name": "Tuomas Tammela",
      "orcid": "0000-0003-3675-6961"
    },
    {
      "affs": [
        14,
        15,
        16
      ],
      "name": "Antonis E. Koromilas",
      "orcid": "0000-0003-1972-0799"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3g9tgpcvyvznz.bib",
  "cited_by": 8,
  "doi": "10.1038/s41556-026-01991-z",
  "fulltext_url": null,
  "id": "3g9tgpcvyvznz",
  "issns": [
    "1465-7392",
    "1476-4679"
  ],
  "landing_url": "https://doi.org/10.1038/s41556-026-01991-z",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1307|Endoplasmic Reticulum Stress and Disease"
    ]
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  "openalex": "W7164821068",
  "pdf_url": null,
  "pmcid": "PMC11844398",
  "pmid": "39990365",
  "published": "2026-06-15",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/3g9tgpcvyvznz.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:07Z",
      "native_id": "W7164821068",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41556-026-01991-z"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1307|Endoplasmic Reticulum Stress and Disease",
      "subfield": "cell-biology"
    }
  ],
  "title": "Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution",
  "title_text": "Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T13:21:07Z",
  "url": "https://research.draconitic.com/paper/3g9tgpcvyvznz",
  "venue": "Nature Cell Biology",
  "versions": []
}