Abstract

<div>Abstract<p>The endoderm-lineage transcription factor FOXA2 has been shown to inhibit lung tumorigenesis in <i>in vitro</i> 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 <i>in vivo</i>, here, we conditionally induced the expression of FOXA2 along with either of the two major lung cancer oncogenes, EGFR<sup>L858R</sup> or KRAS<sup>G12D</sup>, in the lung epithelium of transgenic mice. Notably, FOXA2 suppressed autochthonous lung tumor development driven by EGFR<sup>L858R</sup>, whereas FOXA2 promoted tumor growth driven by KRAS<sup>G12D</sup>. Importantly, FOXA2 expression along with KRAS<sup>G12D</sup> 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 <i>in vivo</i> and human lung cancer cells <i>in vitro</i>, 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 <i>MUC5AC</i> 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 <i>KRAS</i> mutation.</p>Significance:<p>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.</p></div>

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