内胚层谱系转录因子FOXA2已被证明能够通过使用肺癌细胞系进行体外和异种移植研究抑制肺肿瘤生成。然而，在原发性肺肿瘤中，FOXA2的表达与患者生存率改善无关，FOXA2在原发性肺肿瘤中的功能作用仍不清楚。为了了解FOXA2在原发性肺肿瘤中的作用，我们在转基因小鼠的肺泡上皮细胞中条件诱导了FOXA2的表达以及肺癌发生的两种主要癌基因之一EGFRL858R或KRASG12D。值得注意的是，FOXA2抑制了由EGFRL858R驱动的原发性肺肿瘤发展，而FOXA2促进了由KRASG12D驱动的肿瘤生长。重要的是，FOXA2与KRASG12D的共同表达产生了侵袭性黏液腺癌（IMA），一种致命的产粘液的肺癌，约占人类肺癌病例的5％。在小鼠模型中，在体内和体外的人类肺癌细胞中，FOXA2激活了涉及关键粘液转录因子SPDEF的基因调节网络，并上调了MUC5AC，其表达对于诱导IMA至关重要。与仅有FOXA2诱导的相比，FOXA2与突变的KRAS同时表达协同诱导MUC5AC的表达。结合CRISPR干扰的ChIP-seq表明，FOXA2直接结合到MUC5AC的增强子区域并引起H3K27ac增强子标记。此外，FOXA2在人类IMA的原发性肿瘤中表达高水平。总体而言，这项研究揭示了FOXA2不仅是生物标志物，而且还是在KRAS突变存在下IMA的驱动因素。FOXA2的表达结合突变KRAS通过协同促进粘液转录程序来驱动侵袭性黏液腺癌的发生，这表明了针对缺乏有效治疗方法的这种肺癌类型的策略。 ©2023美国肿瘤研究协会。

The endoderm-lineage transcription factor FOXA2 has been shown to inhibit lung tumorigenesis in in vitro and xenograft studies using lung cancer cell lines. However, FOXA2 expression in primary lung tumors does not correlate with an improved patient survival rate, and the functional role of FOXA2 in primary lung tumors remains elusive. To understand the role of FOXA2 in primary lung tumors in vivo, here, we conditionally induced the expression of FOXA2 along with either of the two major lung cancer oncogenes, EGFRL858R or KRASG12D, in the lung epithelium of transgenic mice. Notably, FOXA2 suppressed autochthonous lung tumor development driven by EGFRL858R, whereas FOXA2 promoted tumor growth driven by KRASG12D. Importantly, FOXA2 expression along with KRASG12D produced invasive mucinous adenocarcinoma (IMA) of the lung, a fatal mucus-producing lung cancer comprising approximately 5% of human lung cancer cases. In the mouse model in vivo and human lung cancer cells in vitro, FOXA2 activated a gene regulatory network involved in the key mucous transcription factor SPDEF and upregulated MUC5AC, whose expression is critical for inducing IMA. Coexpression of FOXA2 with mutant KRAS synergistically induced MUC5AC expression compared with that induced by FOXA2 alone. ChIP-seq combined with CRISPR interference indicated that FOXA2 bound directly to the enhancer region of MUC5AC and induced the H3K27ac enhancer mark. Furthermore, FOXA2 was found to be highly expressed in primary tumors of human IMA. Collectively, this study reveals that FOXA2 is not only a biomarker but also a driver for IMA in the presence of a KRAS mutation.FOXA2 expression combined with mutant KRAS drives invasive mucinous adenocarcinoma of the lung by synergistically promoting a mucous transcriptional program, suggesting strategies for targeting this lung cancer type that lacks effective therapies.©2023 American Association for Cancer Research.