Haikuo Zhang, Dana-Farber Cancer Institute
Christine Fillmore Brainson, University of KentuckyFollow
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
Carolina Garcia-de-Alba, Boston Children's Hospital
Margherita Paschini, Boston Children's Hospital
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
Stephanie J. Tuminello, 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, Harvard University
Sangeetha Palakurthi, Dana-Farber Cancer Institute
Lynette M. Sholl, Dana-Farber Cancer Institute
Anil K. Rustgi, University of Pennsylvania
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
Glenn Dranoff, Dana-Farber Cancer Institute
Peter S. Hammerman, Dana-Farber Cancer Institute
Hongbin Ji, Chinese Academy of Sciences, China
Nabeel Bardeesy, Massachusetts General Hospital
Dieter Saur, Technische Universität München, Germany
Hideo Watanabe, Dana-Farber Cancer Institute
Carla F. Kim, Boston Children's Hospital
Kwok-Kin Wong, Dana-Farber Cancer Institute


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.

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Notes/Citation Information

Published in Nature Communications, v. 8, article number: 14922, p. 1-14.

© The Author(s) 2017

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This work was supported in part by PF-12-151-01-DMC from the American Cancer Society, the Uniting Against Lung Cancer Young Investigator Award and NCI K22 CA201036 (to C.F.B.), R01 HL090136, R01 HL132266, R01 HL125821, U01 HL100402 RFA-HL-09-004, American Cancer Society Research Scholar Grant RSG-08-082-01-MGO, the V Foundation for Cancer Research, a Basil O’Conner March of Dimes Starter Award and the Harvard Stem Cell Institute (to C.F.K.), the NIH/NCI P01 CA120964, 5R01CA163896-04, 1R01CA195740-01, 5R01CA140594-07, 5R01CA122794-10 and 5R01CA166480-04 grants and Support from Gross-Loh Family Fund for Lung Cancer Research and Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute (to K.K.W.).

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