ArticleNature communications2017
Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.
Erratum issuedOpen access · goldAbstract read
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Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 88 papers.
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88citing papers in PubMed
4.3field-weighted citation impact, top 5% of its field
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Who cites it
88 citing papers in PubMed, 120 citations in OpenAlex.
- Genes, fuel, and fate in lung cancer.Biochemical Society transactions · 2026Review
- Polycomb scaffolding subunit EED supports the SCLC neuroendocrine identity and EGFR-mutant LUAD-to-SCLC transformation.The Journal of clinical investigation · 2026Article
- Epigenetic reprogramming of lineage switching in cancer.FEBS letters · 2026Review
- Molecular insights and therapeutic implications for the tumor suppressor role of LKB1 in non-small cell lung cancer.Cancer letters · 2026Review
- KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition.Cell death and differentiation · 2026Article
- Research Advances and Disease Modeling in Respiratory Organoids.Biomedicines · 2026Review
- Tumor suppressors LKB1 and SMARCA4 functionally interact to regulate gene expression across diverse biological processes in lung cancer.Frontiers in cell and developmental biology · 2026Article
- TMPRSS11B promotes an acidified microenvironment and immune suppression in squamous lung cancer.EMBO reports · 2025Article
- Lineage plasticity and histological transformation: tumor histology as a spectrum.Cell research · 2025Review
- Histologic Transformation in Cancer: The Path for Clinical Translation.Cancer discovery · 2025Review
- Persistent lineage plasticity driving lung cancer development and progression.Clinical and translational medicine · 2025Review
- Involvement of KEAP1/NRF2 pathway in non-BRAF mutated squamous cell carcinoma of the thyroid.The Journal of pathology · 2025Article
- Tumor suppressors in Sox2-mediated lung cancers promote distinct cell-intrinsic and immunologic remodeling.JCI insight · 2025Article
- LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.Nature communications · 2025Article
- Glycogen drives tumour initiation and progression in lung adenocarcinoma.Nature metabolism · 2025Article
- Mechanisms of Resistance to KRAS Inhibitors: Cancer Cells' Strategic Use of Normal Cellular Mechanisms to Adapt.Cancer science · 2025Review
- Squamous cell cancers of the aero-upper digestive tract: A unified perspective on biology, genetics, and therapy.Cancer cell · 2025Review
- Unraveling the immune mechanisms and therapeutic targets in lung adenosquamous transformation.Frontiers in immunology · 2025Review
- The molecular features of lung cancer stem cells in dedifferentiation process-driven epigenetic alterations.The Journal of biological chemistry · 2024Review
- Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma.iScience · 2024Article
28 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
34 authors at 12 institutions in 3 countries.
Haikuo ZhangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Christine Fillmore BrainsonStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Shohei KoyamaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Amanda J RedigDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Ting ChenDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Shuai LiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Manav GuptaStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Carolina Garcia-de-AlbaStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Margherita PaschiniStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Grit S Herter-SprieDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Gang LuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Xin ZhangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Bryan P MarshStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Stephanie J TuminelloDepartment of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Chunxiao XuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Zhao ChenDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Xiaoen WangDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Esra A AkbayDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Mei ZhengDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sangeetha PalakurthiBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Lynette M ShollDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Anil K RustgiUniversity of Pennsylvania Perelman School of Medicine, Division of Gastroenterology, Department of Medicine and Genetics, Abramson Cancer Center, Philadelphia, Pennsylvania 19104, USA.
David J KwiatkowskiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
J Alan DiehlDepartment of Biochemical and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Adam J BassDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Norman E SharplessUniversity of North Carolina Lineberger Comprehensive Cancer Center, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.
Glenn DranoffDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Peter S HammermanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Hongbin JiKey Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Nabeel BardeesyCancer Center, Massachusetts General Hospital, Boston, Massachusetts 02144, USA.
Dieter SaurDepartment of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München 81675, Germany.
Hideo WatanabeBelfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Carla F KimStem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Kwok-Kin WongDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Dana-Farber Cancer Institute · USHarvard University · USBrigham and Women's Hospital · USBoston Children's Hospital · USCenter for Excellence in Molecular Cell Science · CNDeutschen Konsortium für Translationale Krebsforschung · DEHarvard Stem Cell Institute · USMassachusetts General Hospital · USMedical University of South Carolina · USSleepMed · USUNC Lineberger Comprehensive Cancer CenterUniversity of Pennsylvania · US
Funding
Translational Science Laboratory Shared ResourceP30CA138313 · NCI · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI Jian Ouyang · 2009 to 2026
$42.7MTuberous Sclerosis-Pathway and PathogenesisP01CA120964 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI David J. Kwiatkowski · 2007 to 2026
$35.9MTransformed Esophageal Epithelial Cells and the Tumor MicroenvironmentP01CA098101 · NCI · UNIVERSITY OF PENNSYLVANIA · PI RUSTGI, ANIL K · 2003 to 2023
$31.7MMUC1-C Oncoprotein Evades Immune Destruction in Non-small Cell Lung CancerR01CA166480 · NCI · DANA-FARBER CANCER INST · PI KUFE, DONALD W., WONG, KWOK KIN · 2012 to 2021
$6.3MTherapeutic strategies for specific subsets of KRAS mutant lung cancersR01CA140594 · NCI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI WONG, KWOK KIN · 2009 to 2017
$4.5MIn vivo analysis of EGFR mutant driven lung cancers responses to radiation therapR01CA122794 · NCI · DANA-FARBER CANCER INST · PI WONG, KWOK KIN · 2006 to 2015
$2.8MIn vivo murine models of metastasis for therapeutic testingR01CA163896 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SHARPLESS, NORMAN E, WONG, KWOK KIN · 2012 to 2016
$2.0MIn Vivo and In Vitro Characterization of Bronchio-Alveolar Stem CellsR01HL090136 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI KIM, CARLA F. · 2007 to 2010
$1.9MSignaling pathways in lung stem cell differentiationR01HL125821 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI KIM, CARLA F. · 2015 to 2018
$1.8MCredentialing Mouse Models for Immune System Therapy ResearchR01CA195740 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI PEROU, CHARLES M, WONG, KWOK KIN · 2015 to 2017
$1.8MMouse Models of Metastatic Triple-Negative Breast Cancer for Therapeutic TestingR01CA195754 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI PEROU, CHARLES M, ROSEN, JEFFREY MARK · 2015 to 2017
$1.7MMechanisms of Thrombospondin-1 as a pulmonary vascular mediatorR01HL132266 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI KIM, CARLA F. · 2017 to 2020
$1.6MEuropean Research Council 648521NCI NIH HHS K22 CA201036NCI NIH HHS P01 CA098101NCI NIH HHS P01 CA120964NCI NIH HHS P30 CA138313NCI NIH HHS R01 CA122794NCI NIH HHS R01 CA140594NCI NIH HHS R01 CA163896NCI NIH HHS R01 CA166480NCI NIH HHS R01 CA195740NCI NIH HHS R01 CA195754NHLBI NIH HHS R01 HL090136NHLBI NIH HHS R01 HL125821NHLBI NIH HHS R01 HL132266
Abstract
Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.
Indexed as
AdenocarcinomaAMP-Activated Protein KinasesAnimalsCarcinoma, Squamous CellEnhancer of Zeste Homolog 2 ProteinGene Expression ProfilingGene Expression Regulation, NeoplasticHistonesKaplan-Meier EstimateLung NeoplasmsMethylationMice, 129 StrainMice, KnockoutPolycomb Repressive Complex 2Protein Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)AMP-Activated Protein KinasesEnhancer of Zeste Homolog 2 ProteinHistonesHras protein, mousePolycomb Repressive Complex 2Protein Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)Stk11 protein, mouse
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