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

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 Zhang, Bryan P. Marsh, Stephanie J. Tuminello, Chunxiao Xu, Zhao Chen, Xiaoen Wang, Esra A. Akbay, Mei Zheng, Sangeetha Palakurthi, Lynette M. Sholl, Anil K. Rustgi, David J. Kwiatkowski, J Alan Diehl, Adam J. Bass, Norman E. Sharpless, Glenn Dranoff, Peter S. Hammerman, Hongbin Ji, Nabeel Bardeesy, Dieter Saur, Hideo Watanabe, Carla F. Kim () and Kwok-Kin Wong ()
Additional contact information
Haikuo Zhang: Dana-Farber Cancer Institute
Christine Fillmore Brainson: Boston Children’s Hospital Boston
Shohei Koyama: Dana-Farber Cancer Institute
Amanda J. Redig: Dana-Farber Cancer Institute
Ting Chen: Dana-Farber Cancer Institute
Shuai Li: Dana-Farber Cancer Institute
Manav Gupta: Boston Children’s Hospital Boston
Carolina Garcia- de-Alba: Boston Children’s Hospital Boston
Margherita Paschini: Boston Children’s Hospital Boston
Grit S. Herter-Sprie: Dana-Farber Cancer Institute
Gang Lu: Dana-Farber Cancer Institute
Xin Zhang: Dana-Farber Cancer Institute
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
Zhao Chen: Dana-Farber Cancer Institute
Xiaoen Wang: Dana-Farber Cancer Institute
Esra A. Akbay: Dana-Farber Cancer Institute
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
Anil K. Rustgi: University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center
David J. Kwiatkowski: Dana-Farber Cancer Institute
J Alan Diehl: Medical University of South Carolina
Adam J. Bass: Dana-Farber Cancer Institute
Norman E. Sharpless: University of North Carolina Lineberger Comprehensive Cancer Center, UNC School of Medicine
Glenn Dranoff: Dana-Farber Cancer Institute
Peter S. Hammerman: Dana-Farber Cancer Institute
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
Nabeel Bardeesy: Cancer Center, Massachusetts General Hospital
Dieter Saur: Klinikum rechts der Isar, Technische Universität München
Hideo Watanabe: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute
Carla F. Kim: Boston Children’s Hospital Boston
Kwok-Kin Wong: Dana-Farber Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14922

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