IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v8y2017i1d10.1038_ncomms14922.html
   My bibliography  Save this article

Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2

Author

Listed:
  • Haikuo Zhang

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Christine Fillmore Brainson

    (Boston Children’s Hospital Boston
    Harvard Medical School
    Harvard Stem Cell Institute
    †Present address: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 04536, USA.)

  • Shohei Koyama

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Amanda J. Redig

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Ting Chen

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Shuai Li

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Manav Gupta

    (Boston Children’s Hospital Boston
    Harvard Medical School
    Harvard Stem Cell Institute)

  • Carolina Garcia-de-Alba

    (Boston Children’s Hospital Boston
    Harvard Medical School
    Harvard Stem Cell Institute)

  • Margherita Paschini

    (Boston Children’s Hospital Boston
    Harvard Medical School
    Harvard Stem Cell Institute)

  • Grit S. Herter-Sprie

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Gang Lu

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Xin Zhang

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Bryan P. Marsh

    (Boston Children’s Hospital Boston)

  • Stephanie J. Tuminello

    (Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Chunxiao Xu

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Zhao Chen

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Xiaoen Wang

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Esra A. Akbay

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Mei Zheng

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Sangeetha Palakurthi

    (Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute)

  • Lynette M. Sholl

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Anil K. Rustgi

    (University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center)

  • David J. Kwiatkowski

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • J Alan Diehl

    (Medical University of South Carolina)

  • Adam J. Bass

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Norman E. Sharpless

    (University of North Carolina Lineberger Comprehensive Cancer Center, UNC School of Medicine)

  • Glenn Dranoff

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Peter S. Hammerman

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School)

  • Hongbin Ji

    (Key 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
    School of Life Science and Technology, Shanghai Tech University)

  • Nabeel Bardeesy

    (Cancer Center, Massachusetts General Hospital)

  • Dieter Saur

    (Klinikum rechts der Isar, Technische Universität München
    German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK))

  • Hideo Watanabe

    (Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute)

  • Carla F. Kim

    (Boston Children’s Hospital Boston
    Harvard Medical School
    Harvard Stem Cell Institute)

  • Kwok-Kin Wong

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital, Harvard Medical School
    Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
    Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center)

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.

Suggested Citation

  • Haikuo Zhang & Christine Fillmore Brainson & Shohei Koyama & Amanda J. Redig & Ting Chen & Shuai Li & Manav Gupta & Carolina Garcia-de-Alba & Margherita Paschini & Grit S. Herter-Sprie & Gang Lu & Xin, 2017. "Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14922
    DOI: 10.1038/ncomms14922
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms14922
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms14922?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Lindsey R. Conroy & Harrison A. Clarke & Derek B. Allison & Samuel Santos Valenca & Qi Sun & Tara R. Hawkinson & Lyndsay E. A. Young & Juanita E. Ferreira & Autumn V. Hammonds & Jaclyn B. Dunne & Robe, 2023. "Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Fan Chen & Aria L. Byrd & Jinpeng Liu & Robert M. Flight & Tanner J. DuCote & Kassandra J. Naughton & Xiulong Song & Abigail R. Edgin & Alexsandr Lukyanchuk & Danielle T. Dixon & Christian M. Gosser &, 2023. "Polycomb deficiency drives a FOXP2-high aggressive state targetable by epigenetic inhibitors," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14922. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.