Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2
Open accessAbstract
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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LKB1 loss promotes tumorigenesis by reprogramming epigenetic states, facilitating lineage plasticity and promoting metastasis.
“Beyond its role regulating metabolism via AMPK, LKB1 loss promotes tumorigenesis by reprogramming epigenetic states, facilitating lineage plasticity and promoting metastasis22,67–70.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [68]
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Self-citationLKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers
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- Authors
- Zhang, H., Fillmore Brainson, C., 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., Palakurthi, S., Sholl, L. M., Rustgi, A. K., Kwiatkowski, D. J., Diehl, J. A., Bass, A. J., Sharpless, N. E., Dranoff, G., Hammerman, P. S., Ji, H., Bardeesy, N., Saur, D., Watanabe, H., Kim, C. F., & Wong, K.-K.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Tisch Cancer Institute (US)
- Dana-Farber Cancer Institute (US)
- Abramson Cancer Center (US)
- Medical University of South Carolina (US)
- University of North Carolina at Chapel Hill (US)
- Chinese Academy of Sciences (CN)
- Massachusetts General Hospital (US)
- German Cancer Research Center (DE)
- Corresponding author
- Kim, Carla F.
- Wong, Kwok-Kin
- ORCID
- Zhang, Haikuo
- Koyama, Shohei
- Chen, Ting
- Li, Shuai
- Gupta, Manav
- Paschini, Margherita
- Herter-Sprie, Grit S.
- 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
- Venue
- Nature Communications
- Published
- 2017-04-07
- Volume
- 8
- Issue
- 1
- Pages
- 14922-14922
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5385585
- OpenAlex
- W2604498317
- Cited by
- 127
- References
- 7
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 18 · 2023: 16 · 2022: 13 · 2021: 16 · 2020: 16 · 2019: 12 · 2018: 7 · 2017: 4
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-06-09)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- UNC Libraries
- Funders
- American Cancer Society
- March of Dimes Foundation
- V Foundation for Cancer Research
- Uniting Against Lung Cancer
- National Institutes of Health (RFA-HL-09-004, CA120964)
- Harvard Stem Cell Institute
- National Heart, Lung, and Blood Institute (U01HL100402, R01HL125821, R01HL132266, R01HL090136)
- National Cancer Institute (R01CA166480, K22CA201036, P01CA098101, CA120964, R01CA122794, R01CA195740, R01CA140594, R01CA195754, R01CA163896, P01CA120964, P30CA138313)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- LKB1, STK11, lung cancer, lineage switch, KRAS, squamous cell carcinoma, lung adenocarcinoma, polycomb repressive complex 2, EZH2, H3K27me3, H3K27ac, H3K4me3, EED, cellular plasticity, BASC, Clara cells, epigenetics
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Adenocarcinoma, Animals, Carcinoma, Squamous Cell, Histones, Lung Neoplasms, Methylation, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, Mice, Knockout, Gene Expression Profiling, Kaplan-Meier Estimate, AMP-Activated Protein Kinases, Mice, 129 Strain, Polycomb Repressive Complex 2
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