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 PalakurthiLynette 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 journalArticlepeer-review

37 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 languageEnglish (US)
Article number14922
JournalNature communications
Volume8
DOIs
StatePublished - Apr 7 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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