癌细胞改变其身份的能力对于肿瘤的生存和进展至关重要。 KRAS 驱动的肺腺癌 (LUAD) 中肺谱系特异性因子 NKX2-1 的缺失会促进肿瘤进展，并导致肺至胃谱系转换，该转换依赖于先锋因子 FoxA1 和 FoxA2 的活性；然而，其根本机制仍然很大程度上未知。在这里，我们证明 FoxA1/2 重新编程 NKX2-1 阴性 LUAD 的表观遗传景观，以促进胃身份。 Nkx2-1 缺失后，FoxA1/2 通过招募 TET3（一种诱导 DNA 去甲基化的酶）来介导胃定义基因的去甲基化。 H3K27ac ChIP-seq 和 HiChIP 显示 FoxA1/2 还控制调节元件的活性及其在胃位点的 3D 相互作用。此外，FoxA1/2 依赖性表观遗传重编程需要致癌 KRAS。这项工作证明了 FoxA1/2 在重新连接甲基化和组蛋白景观以及 NKX2-1 阴性 LUAD 的顺式调节动力学以驱动癌细胞谱系转换中的作用。

The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric identity. After Nkx2-1 deletion, FoxA1/2 mediate demethylation of gastric-defining genes through recruitment of TET3, an enzyme that induces DNA demethylation. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of regulatory elements and their 3D interactions at gastric loci. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.