1. Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.
- Author
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Zhang H, Fillmore Brainson C, 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 D, Watanabe H, Kim CF, and Wong KK
- Subjects
- AMP-Activated Protein Kinases, Adenocarcinoma metabolism, Adenocarcinoma pathology, Animals, 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 metabolism, Lung Neoplasms pathology, Methylation, Mice, 129 Strain, Mice, Knockout, Polycomb Repressive Complex 2 metabolism, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Tumor Cells, Cultured, Adenocarcinoma genetics, Carcinoma, Squamous Cell genetics, Lung Neoplasms genetics, Polycomb Repressive Complex 2 genetics, Protein Serine-Threonine Kinases genetics
- 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.
- Published
- 2017
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