Abstract 1479: FOXA2 induces invasive mucinous adenocarcinoma of the lung in the presence of mutant KRAS

Abstract Introduction: The role of the endoderm lineage transcription factor FOXA2 in autochthonous lung tumors has been elusive though the expression of FOXA2 has been reported in human lung cancers. Here, using GEMM (Genetically Engineered Mouse Models) and human lung cancer cell lines, we delineate the role of FOXA2 in lung cancers. Experimental Procedures: GEMM that carry mutant KRAS or mutant EGFR along with FOXA2 (CCSP-rtTA; tetO-Foxa2; tetO-Kras.G12D or tetO-EGFR.L858R) were developed allowing for lung tumor induction by doxycycline administration. The growth of lung tumors affected by FOXA2 was assessed by microCT and pathologically. FOXA2 downstream genes were also evaluated in vivo by immunohistochemistry of mouse lung sections and in vitro by gain (ectopic lentivirus transduction) and loss (siRNA) of function approaches with human lung cancer cell lines using TaqMan gene expression, RNA-seq, ChIP-seq and CRISPRi analyses. FOXA2 protein expression in human lung cancer specimens was also assessed. Data: FOXA2 suppressed the growth of EGFR-mutant lung tumors while promoting that of KRAS-mutant lung tumors in GEMM. Notably, half of the KRAS-mutant lung tumors presented invasive mucinous adenocarcinoma of the lung (IMA) with the expression of a master mucous transcription factor SPDEF and the two major IMA mucin genes MUC5AC and MUC5B. In vitro, FOXA2 induced the expression of SPDEF, MUC5AC and MUC5B by directly binding to their loci. H3K27ac was introduced at the enhancer region of MUC5AC (most highly expressed IMA gene) by FOXA2 and the expression of MUC5AC initiated by FOXA2 was enhanced by mutant KRAS. FOXA2 was highly expressed in human IMA compared to normal lung. Conclusions: FOXA2 induces IMA in the presence of mutant KRAS by directly regulating the expression of mucous genes. Citation Format: Yutaka Maeda, Koichi Tomoshige, William D. Stuart, Iris M. Fink-Baldauf, Masaoki Ito, Tomoshi Tsuchiya, Takeshi Nagayasu, Tomoki Yamatsuji, Morihito Okada, Takuya Fukazawa, Minzhe Guo. FOXA2 induces invasive mucinous adenocarcinoma of the lung in the presence of mutant KRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1479.