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

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

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

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.

Original language	English
Article number	14922
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14922
State	Published - Apr 7 2017

Bibliographical note

Funding Information:
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.).

Funding

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.).

Funders	Funder number
V Foundation for Cancer Research
Harvard Stem Cell Institute
Basil O'Conner March of Dimes Starter Award
National Institutes of Health (NIH)
American Cancer Society-Michigan Cancer Research Fund
Dana-Farber Cancer Institute
National Heart, Lung, and Blood Institute (NHLBI)	R01HL090136, R01HL132266, R01HL125821
National Childhood Cancer Registry – National Cancer Institute	R01CA140594, P01CA098101, P30CA138313, U01 HL100402 RFA-HL-09-004, R01CA195754, RSG-08-082-01-MGO, P01CA120964, R01CA163896, R01CA195740, R01CA122794, K22CA201036, R01CA166480
Horizon 2020 Framework Programme	648521

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms14922

Cite this

Zhang, H., Brainson, C. F., Koyama, S., Redig, A. J., Chen, T., Li, S., Gupta, M., Garcia-De-Alba, C., Paschini, M., Herter-Sprie, G. S., Lu, G., Zhang, X., Marsh, B. P., Tuminello, S. J., Xu, C., Chen, Z., Wang, X., Akbay, E. A., Zheng, M., ... Wong, K. K. (2017). Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2. Nature Communications, 8, Article 14922. https://doi.org/10.1038/ncomms14922

@article{64451aa9bece42b3a7a63e76ea1d518a,

title = "Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2",

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.",

author = "Haikuo Zhang and Brainson, \{Christine Fillmore\} and Shohei Koyama and Redig, \{Amanda J.\} and Ting Chen and Shuai Li and Manav Gupta and Carolina Garcia-De-Alba and Margherita Paschini and Herter-Sprie, \{Grit S.\} and Gang Lu and Xin Zhang and Marsh, \{Bryan P.\} and Tuminello, \{Stephanie J.\} and Chunxiao Xu and Zhao Chen and Xiaoen Wang and Akbay, \{Esra A.\} and Mei Zheng and Sangeetha Palakurthi and Sholl, \{Lynette M.\} and Rustgi, \{Anil K.\} and Kwiatkowski, \{David J.\} and DIehl, \{J. Alan\} and Bass, \{Adam J.\} and Sharpless, \{Norman E.\} and Glenn Dranoff and Hammerman, \{Peter S.\} and Hongbin Ji and Nabeel Bardeesy and DIeter Saur and Hideo Watanabe and Kim, \{Carla F.\} and Wong, \{Kwok Kin\}",

note = "Funding Information: 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.).",

year = "2017",

month = apr,

day = "7",

doi = "10.1038/ncomms14922",

language = "English",

volume = "8",

}

Zhang, H, Brainson, CF, Koyama, S, Redig, AJ, Chen, T, Li, S, Gupta, M, Garcia-De-Alba, C, Paschini, M, Herter-Sprie, GS, Lu, G, Zhang, X, Marsh, BP, Tuminello, SJ, Xu, C, Chen, Z, Wang, X, Akbay, EA, Zheng, M, Palakurthi, S, Sholl, LM, Rustgi, AK, Kwiatkowski, DJ, DIehl, JA, Bass, AJ, Sharpless, NE, Dranoff, G, Hammerman, PS, Ji, H, Bardeesy, N, Saur, DI, Watanabe, H, Kim, CF & Wong, KK 2017, 'Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2', Nature Communications, vol. 8, 14922. https://doi.org/10.1038/ncomms14922

TY - JOUR

T1 - Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2

AU - Zhang, Haikuo

AU - Brainson, Christine Fillmore

AU - Koyama, Shohei

AU - Redig, Amanda J.

AU - Chen, Ting

AU - Li, Shuai

AU - Gupta, Manav

AU - Garcia-De-Alba, Carolina

AU - Paschini, Margherita

AU - Herter-Sprie, Grit S.

AU - Lu, Gang

AU - Zhang, Xin

AU - Marsh, Bryan P.

AU - Tuminello, Stephanie J.

AU - Xu, Chunxiao

AU - Chen, Zhao

AU - Wang, Xiaoen

AU - Akbay, Esra A.

AU - Zheng, Mei

AU - Palakurthi, Sangeetha

AU - Sholl, Lynette M.

AU - Rustgi, Anil K.

AU - Kwiatkowski, David J.

AU - DIehl, J. Alan

AU - Bass, Adam J.

AU - Sharpless, Norman E.

AU - Dranoff, Glenn

AU - Hammerman, Peter S.

AU - Ji, Hongbin

AU - Bardeesy, Nabeel

AU - Saur, DIeter

AU - Watanabe, Hideo

AU - Kim, Carla F.

AU - Wong, Kwok Kin

N1 - Funding Information: 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.).

PY - 2017/4/7

Y1 - 2017/4/7

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85017222703

UR - https://www.scopus.com/pages/publications/85017222703#tab=citedBy

U2 - 10.1038/ncomms14922

DO - 10.1038/ncomms14922

M3 - Article

C2 - 28387316

AN - SCOPUS:85017222703

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14922

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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