Cargando…
Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385585/ https://www.ncbi.nlm.nih.gov/pubmed/28387316 http://dx.doi.org/10.1038/ncomms14922 |
_version_ | 1782520628896595968 |
---|---|
author | Zhang, Haikuo Fillmore Brainson, Christine Koyama, Shohei Redig, Amanda J. Chen, Ting Li, Shuai Gupta, Manav Garcia-de-Alba, Carolina Paschini, Margherita Herter-Sprie, Grit S. Lu, Gang Zhang, Xin Marsh, Bryan P. Tuminello, Stephanie J. Xu, Chunxiao Chen, Zhao Wang, Xiaoen Akbay, Esra A. Zheng, Mei Palakurthi, Sangeetha Sholl, Lynette M. Rustgi, Anil K. Kwiatkowski, David J. Diehl, J Alan Bass, Adam J. Sharpless, Norman E. Dranoff, Glenn Hammerman, Peter S. Ji, Hongbin Bardeesy, Nabeel Saur, Dieter Watanabe, Hideo Kim, Carla F. Wong, Kwok-Kin |
author_facet | Zhang, Haikuo Fillmore Brainson, Christine Koyama, Shohei Redig, Amanda J. Chen, Ting Li, Shuai Gupta, Manav Garcia-de-Alba, Carolina Paschini, Margherita Herter-Sprie, Grit S. Lu, Gang Zhang, Xin Marsh, Bryan P. Tuminello, Stephanie J. Xu, Chunxiao Chen, Zhao Wang, Xiaoen Akbay, Esra A. Zheng, Mei Palakurthi, Sangeetha Sholl, Lynette M. Rustgi, Anil K. Kwiatkowski, David J. Diehl, J Alan Bass, Adam J. Sharpless, Norman E. Dranoff, Glenn Hammerman, Peter S. Ji, Hongbin Bardeesy, Nabeel Saur, Dieter Watanabe, Hideo Kim, Carla F. Wong, Kwok-Kin |
author_sort | Zhang, Haikuo |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5385585 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53855852017-04-26 Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2 Zhang, Haikuo Fillmore Brainson, Christine Koyama, Shohei Redig, Amanda J. Chen, Ting Li, Shuai Gupta, Manav Garcia-de-Alba, Carolina Paschini, Margherita Herter-Sprie, Grit S. Lu, Gang Zhang, Xin Marsh, Bryan P. Tuminello, Stephanie J. Xu, Chunxiao Chen, Zhao Wang, Xiaoen Akbay, Esra A. Zheng, Mei Palakurthi, Sangeetha Sholl, Lynette M. Rustgi, Anil K. Kwiatkowski, David J. Diehl, J Alan Bass, Adam J. Sharpless, Norman E. Dranoff, Glenn Hammerman, Peter S. Ji, Hongbin Bardeesy, Nabeel Saur, Dieter Watanabe, Hideo Kim, Carla F. Wong, Kwok-Kin Nat Commun Article 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. Nature Publishing Group 2017-04-07 /pmc/articles/PMC5385585/ /pubmed/28387316 http://dx.doi.org/10.1038/ncomms14922 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Zhang, Haikuo Fillmore Brainson, Christine Koyama, Shohei Redig, Amanda J. Chen, Ting Li, Shuai Gupta, Manav Garcia-de-Alba, Carolina Paschini, Margherita Herter-Sprie, Grit S. Lu, Gang Zhang, Xin Marsh, Bryan P. Tuminello, Stephanie J. Xu, Chunxiao Chen, Zhao Wang, Xiaoen Akbay, Esra A. Zheng, Mei Palakurthi, Sangeetha Sholl, Lynette M. Rustgi, Anil K. Kwiatkowski, David J. Diehl, J Alan Bass, Adam J. Sharpless, Norman E. Dranoff, Glenn Hammerman, Peter S. Ji, Hongbin Bardeesy, Nabeel Saur, Dieter Watanabe, Hideo Kim, Carla F. Wong, Kwok-Kin Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2 |
title | Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2 |
title_full | Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2 |
title_fullStr | Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2 |
title_full_unstemmed | Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2 |
title_short | Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2 |
title_sort | lkb1 inactivation drives lung cancer lineage switching governed by polycomb repressive complex 2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385585/ https://www.ncbi.nlm.nih.gov/pubmed/28387316 http://dx.doi.org/10.1038/ncomms14922 |
work_keys_str_mv | AT zhanghaikuo lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT fillmorebrainsonchristine lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT koyamashohei lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT redigamandaj lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT chenting lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT lishuai lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT guptamanav lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT garciadealbacarolina lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT paschinimargherita lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT herterspriegrits lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT lugang lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT zhangxin lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT marshbryanp lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT tuminellostephaniej lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT xuchunxiao lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT chenzhao lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT wangxiaoen lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT akbayesraa lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT zhengmei lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT palakurthisangeetha lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT sholllynettem lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT rustgianilk lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT kwiatkowskidavidj lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT diehljalan lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT bassadamj lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT sharplessnormane lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT dranoffglenn lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT hammermanpeters lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT jihongbin lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT bardeesynabeel lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT saurdieter lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT watanabehideo lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT kimcarlaf lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 AT wongkwokkin lkb1inactivationdriveslungcancerlineageswitchinggovernedbypolycombrepressivecomplex2 |