Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2
Zhang, Haikuo1,2; Brainson, Christine Fillmore3,4,5,6,19; Koyama, Shohei1,2; Redig, Amanda J.1,2; Chen, Ting1,2; Li, Shuai1,2; Gupta, Manav3,4,6; Garcia-de-Alba, Carolina3,4,5,6; Paschini, Margherita3,4,5,6; Herter-Sprie, Grit S.1,2; Lu, Gang1,2; Zhang, Xin1,2; Marsh, Bryan P.3,4; Tuminello, Stephanie J.7; Xu, Chunxiao1,2; Chen, Zhao1,2; Wang, Xiaoen1,2; Akbay, Esra A.1,2; Zheng, Mei2; Palakurthi, Sangeetha8; Sholl, Lynette M.1,2; Rustgi, Anil K.9; Kwiatkowski, David J.1,2; Diehl, J. Alan10; Bass, Adam J.1,2; Sharpless, Norman E.11; Dranoff, Glenn1,2; Hammerman, Peter S.1,2; Ji, Hongbin12,13; Bardeesy, Nabeel14; Saur, Dieter15,16,17; Watanabe, Hideo8; Kim, Carla F.3,4,5,6; Wong, Kwok-Kin1,2,8,18
AbstractAdenosquamous 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, DNp63 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.
Indexed BySCI
Funding ProjectNIH/NCI[P01 CA120964] ; NIH/NCI[5R01CA163896-04] ; NIH/NCI[1R01CA195740-01] ; NIH/NCI[5R01CA140594-07] ; NIH/NCI[5R01CA122794-10] ; NIH/NCI[5R01CA166480-04]
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000398455100001
Original Document TypeArticle
Citation statistics
Cited Times:12[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Corresponding AuthorKim, Carla F.; Wong, Kwok-Kin
Affiliation1.Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA
2.Brigham & Womens Hosp, Harvard Med Sch, Dept Med, Boston, MA 02115 USA
3.Boston Childrens Hosp Boston, Stem Cell Program, Boston, MA 02115 USA
4.Boston Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA
5.Harvard Med Sch, Dept Genet, Boston, MA 02115 USA
6.Harvard Stem Cell Inst, Cambridge, MA 02138 USA
7.Tisch Canc Inst, Icahn Sch Med Mt Sinai, Dept Med, Div Pulm Crit Care & Sleep Med, New York, NY 10029 USA
8.Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA
9.Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Dept Med & Genet,Div Gastroenterol, Philadelphia, PA 19104 USA
10.Univ South Carolina, Dept Biochem & Mol Biol Med, Charleston, SC 29425 USA
11.Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA
12.Chinese Acad Sci, Innovat Ctr Cell Signaling Network, Ctr Excellence Mol Cell Sci, Shanghai Inst Biol Sci,Inst Biochem & Cell Biol,K, Shanghai 200031, Peoples R China
13.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China
14.Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02144 USA
15.Tech Univ Munich, Klinikum Rechts Isar, Dept Internal Med 2, D-81675 Munich, Germany
16.German Canc Res Ctr, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
17.German Canc Consortium DKTK, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
18.NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, New York, NY 10016 USA
19.Univ Kentucky, Dept Toxicol & Canc Biol, Lexington, KY 04536 USA
Recommended Citation
GB/T 7714
Zhang, Haikuo,Brainson, Christine Fillmore,Koyama, Shohei,et al. Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2[J]. NATURE COMMUNICATIONS,2017,8.
APA Zhang, Haikuo.,Brainson, Christine Fillmore.,Koyama, Shohei.,Redig, Amanda J..,Chen, Ting.,...&Wong, Kwok-Kin.(2017).Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.NATURE COMMUNICATIONS,8.
MLA Zhang, Haikuo,et al."Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2".NATURE COMMUNICATIONS 8(2017).
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