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.

中文翻译：

---

FoxA1/2 依赖性表观基因组重编程驱动肺腺癌的谱系转换


癌细胞经历身份变化的能力（即谱系可塑性）在肿瘤进展和对治疗的反应中起着关键作用。在 KRAS 驱动的肺腺癌 （LUAD） 中，肺谱系指示符 NKX2-1 的缺失会加速肿瘤进展并导致 FoxA1/2 依赖性肺系到胃系转换。然而，FoxA1/2 激活肺中潜伏胃身份的机制在很大程度上仍然未知。在这里，我们表明 FoxA1/2 通过促进 10-11 易位 （TET）2/3 募集、DNA 去甲基化、组蛋白 3 赖氨酸 27 乙酰化 （H3K27ac） 沉积和三维 （3D） 染色质相互作用，在小鼠模型中 NKX2-1 丢失后重编程胃特异性基因的表观遗传景观。FoxA1/2 介导的 DNA 甲基化变化在人类内胚层发育以及人类肺和胰腺肿瘤的进展中高度保守。此外，致癌信号转导是 FoxA1/2 依赖性表观遗传重编程的特定元件所必需的。这项工作证明了 FoxA1/2 在重新连接 NKX2-1 阴性 LUAD 的 DNA 甲基化和 3D 染色质景观以驱动癌细胞谱系转换中的作用。