Though invasive
mucinous adenocarcinoma of the lung (IMA) is pathologically distinctive, the molecular mechanism driving IMA is not well understood, which hampers efforts to identify therapeutic targets. Here, by analyzing gene expression profiles of human and mouse IMA, we identified a Mucinous Lung
Tumor Signature of 143 genes, which was unexpectedly enriched in
mucin-producing gastrointestinal, pancreatic, and breast
cancers. The signature genes included
transcription factors FOXA3, SPDEF, HNF4A,
mucins MUC5AC, MUC5B, MUC3, and an inhibitory immune checkpoint VTCN1/B7-H4 (but not PD-L1/B7-H1). Importantly, induction of FOXA3 or SPDEF along with mutant KRAS in lung epithelium was sufficient to develop benign or malignant mucinous lung
tumors, respectively, in transgenic mice. FOXA3 and SPDEF induced MUC5AC and MUC5B, while HNF4A induced MUC3 in human mucinous
lung cancer cells harboring a KRAS mutation. ChIP-seq combined with CRISPR/Cas9 determined that upstream enhancer regions of the
mucin genes MUC5AC and MUC5B, which were bound by SPDEF, were required for the expression of the
mucin genes. Here, we report the molecular signature and gene regulatory network driving mucinous lung
tumors.