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; Kwok-Kin Wong

doi:10.1038/ncomms14922

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

Nat Commun. 2017 Apr 7:8:14922. doi: 10.1038/ncomms14922.

Authors

Haikuo Zhang^{1

2}, Christine Fillmore Brainson^{3

4

5}, Shohei Koyama^{1

2}, Amanda J Redig^{1

2}, Ting Chen^{1

2}, Shuai Li^{1

2}, Manav Gupta^{3

4

5}, Carolina Garcia-de-Alba^{3

4

5}, Margherita Paschini^{3

4

5}, Grit S Herter-Sprie^{1

2}, Gang Lu^{1

2}, Xin Zhang^{1

2}, Bryan P Marsh³, Stephanie J Tuminello⁶, Chunxiao Xu^{1

2}, Zhao Chen^{1

2}, Xiaoen Wang^{1

2}, Esra A Akbay^{1

2}, Mei Zheng², Sangeetha Palakurthi⁷, Lynette M Sholl^{1

2}, Anil K Rustgi⁸, David J Kwiatkowski^{1

2}, J Alan Diehl⁹, Adam J Bass^{1

2}, Norman E Sharpless¹⁰, Glenn Dranoff^{1

2}, Peter S Hammerman^{1

2}, Hongbin Ji^{11

12}, Nabeel Bardeesy¹³, Dieter Saur^{14

15}, Hideo Watanabe⁷, Carla F Kim^{3

4

5}, Kwok-Kin Wong^{1

2

7

16}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
³ Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital Boston, Boston, Massachusetts 02115, USA.
⁴ Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
⁵ Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
⁶ 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.
⁷ Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
⁸ University of Pennsylvania Perelman School of Medicine, Division of Gastroenterology, Department of Medicine and Genetics, Abramson Cancer Center, Philadelphia, Pennsylvania 19104, USA.
⁹ Department of Biochemical and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
¹⁰ University of North Carolina Lineberger Comprehensive Cancer Center, UNC School of Medicine, Chapel Hill, North Carolina 27599, USA.
¹¹ 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.
¹² School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China.
¹³ Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02144, USA.
¹⁴ Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, München 81675, Germany.
¹⁵ German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
¹⁶ Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York 10016, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases
Adenocarcinoma / genetics*
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Animals
Carcinoma, Squamous Cell / genetics*
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / pathology
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Histones / metabolism
Kaplan-Meier Estimate
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Methylation
Mice, 129 Strain
Mice, Knockout
Polycomb Repressive Complex 2 / genetics*
Polycomb Repressive Complex 2 / metabolism
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Tumor Cells, Cultured

Substances

Histones
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2
Protein Serine-Threonine Kinases
Stk11 protein, mouse
AMP-Activated Protein Kinases
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding