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. 2025 Feb 3;60(3):472-489.e8.
doi: 10.1016/j.devcel.2024.10.009. Epub 2024 Nov 7.

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

Katherine Gillis  1 , Walter A Orellana  1 , Emily Wilson  1 , Timothy J Parnell  2 , Gabriela Fort  1 , Pengshu Fang  1 , Headtlove Essel Dadzie  1 , Brandon M Murphy  1 , Xiaoyang Zhang  1 , Eric L Snyder  3
Affiliations

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

Katherine Gillis et al. Dev Cell. .

Abstract

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.

Keywords: FOXA1/2; TET2/3; cancer lineage switching/plasticity; epigenetic reprogramming; lung adenocarcinoma.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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