FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma

The ability of cancer cells to undergo identity changes (i.e., lineage plasticity) plays a key role in tumor progression and response to therapy. Loss of the pulmonary lineage specifier NKX2-1 in KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and causes a FoxA1/2-dependent pulmonary-to-gastric lineage switch. However, the mechanisms by which FoxA1/2 activate a latent gastric identity in the lung remain largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of gastric-specific genes after NKX2-1 loss in mouse models by facilitating ten-eleven translocation (TET)2/3 recruitment, DNA demethylation, histone 3 lysine 27 acetylation (H3K27ac) deposition, and three-dimensional (3D) chromatin interactions. FoxA1/2-mediated DNA methylation changes are highly conserved in human endodermal development and in progression of human lung and pancreatic neoplasia. Furthermore, oncogenic signaling is required for specific elements of FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the DNA methylation and 3D chromatin landscape of NKX2-1-negative LUAD to drive cancer cell lineage switching. [Display omitted] •In vivo NKX2-1 loss alters lineage-specific DNA methylation in lung adenocarcinoma•Recruitment of TET2/3 to regions demethylated upon NKX2-1 loss requires FoxA1/2•FoxA1/2-dependent changes in 3D chromatin structure accompany lineage switching•KRASG12D dictates cell-type-specific DNA methylation in lung adenocarcinoma Gillis et al. use in vivo epigenomic analyses to investigate mechanisms of lineage switching in lung adenocarcinoma (LUAD), finding that NKX2-1, FoxA1, and FoxA2 control lineage-specific DNA methylation, TET2/3 localization, and 3D chromatin structure. They also show that oncogenic KRAS dictates cell-type-specific DNA methylation patterns in NKX2-1-negative LUAD.