title: Gene signature driving invasive mucinous adenocarcinoma of the lung.
abstract: 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 factorsFOXA3, SPDEF, HNF4A,mucinsMUC5AC, MUC5B, MUC3,and an inhibitory immune checkpointVTCN1/B7-H4(but notPD-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 inducedMUC5ACandMUC5B,while HNF4A inducedMUC3in human mucinous lung cancer cells harboring aKRASmutation. ChIP-seq combined with CRISPR/Cas9 determined that upstream enhancer regions of the mucin genesMUC5ACandMUC5B, 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.
authors.affiliation: Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Department of Electrical Engineering and Computing Systems, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Minzhe
authors.initials: M
authors.lastname: Guo
authors.affiliation: Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tomoshige
authors.affiliation: Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.affiliation: Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Tomoshi
authors.initials: T
authors.lastname: Tsuchiya
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.affiliation: Institute of Pathology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.affiliation: Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Fink-Baldauf
authors.affiliation: Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagayasu
authors.affiliation: Department of General Surgery, Kawasaki Medical School, Okayama, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
authors.affiliation: Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
authors.affiliation: Perinatal Institute, Divisions of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA yutaka.maeda@cchmc.org.
authors.forename: Yutaka
authors.identifier: 0000-0002-9537-3971
authors.initials: Y
authors.lastname: Maeda
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000473:pathology*; D000818:Animals; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic
keywords: 
  IMA
  ; 
  SPDEF
  ; FOXA3; MUC5AC/5B; VTCN1