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

Adenosquamous lung tumors may result from cellular plasticity. 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, included 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. We performed chromatin immunoprecipitation (ChIP) on microdissected tumors confirmed to be either ADC or SCC by histology and qPCR. The two activating marks, histone H3 lysine 4 tri-methylation (H3K4me3) and histone H3 lysine 27 acetylation (H3K27ac), and the PRC2 derived silencing mark, histone H3 lysine 27 tri-methylation (H3K27me3) were immunoprecipitated, followed by sequencing the chromatin bound DNA. Examination of 3 different histone modifications in 2 histological subtypes of mouse tumors