title: Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Haikuo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Fillmore Brainson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Redig
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Manav
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Garcia-de-Alba
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Margherita
authors.initials: M
authors.lastname: Paschini
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Marsh
authors.affiliation: Department 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.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Tuminello
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Xiaoen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Palakurthi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Division of Gastroenterology, Department of Medicine and Genetics, Abramson Cancer Center, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Department of Biochemical and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: University of North Carolina Lineberger Comprehensive Cancer Center, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: 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, Shanghai 200031, China.|School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02144, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München 81675, Germany.|German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Hideo
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Carla F
authors.initials: CF
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.|Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York 10016, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D006657:Histones; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)