title: The putative tumor suppressor gene EphA3 fails to demonstrate a crucial role in murine lung tumorigenesis or morphogenesis.
abstract: Treatment of non-small cell lung cancer (NSCLC) is based on histological analysis and molecular profiling of targetable driver oncogenes. Therapeutic responses are further defined by the landscape of passenger mutations, or loss of tumor suppressor genes. We report here a thorough study to address the physiological role of the putative lung cancer tumor suppressor EPH receptor A3 (EPHA3), a gene that is frequently mutated in human lung adenocarcinomas. Our data shows that homozygous or heterozygous loss of EphA3 does not alter the progression of murine adenocarcinomas that result from Kras mutation or loss of Trp53, and we detected negligible postnatal expression of EphA3 in adult wild-type lungs. Yet, EphA3 was expressed in the distal mesenchyme of developing mouse lungs, neighboring the epithelial expression of its Efna1 ligand; this is consistent with the known roles of EPH receptors in embryonic development. However, the partial loss of EphA3 leads only to subtle changes in epithelial Nkx2-1, endothelial Cd31 and mesenchymal Fgf10 RNA expression levels, and no macroscopic phenotypic effects on lung epithelial branching, mesenchymal cell proliferation, or abundance and localization of CD31-positive endothelia. The lack of a discernible lung phenotype in EphA3-null mice might indicate lack of an overt role for EPHA3 in the murine lung, or imply functional redundancy between EPHA receptors. Our study shows how biological complexity can challenge in vivo functional validation of mutations identified in sequencing efforts, and provides an incentive for the design of knock-in or conditional models to assign the role of EPHA3 mutation during lung tumorigenesis.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Lahtela
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Barun
authors.initials: B
authors.lastname: Pradhan
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Katja
authors.initials: K
authors.lastname: Närhi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Annabrita
authors.initials: A
authors.lastname: Hemmes
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki FI-00014, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Särkioja
authors.affiliation: Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki FI-00014, Finland.
authors.forename: Panu E
authors.initials: PE
authors.lastname: Kovanen
authors.affiliation: Spinal Cord Injury Team, Robarts Research Institute, University of Western Ontario, London, ON N6A 5K8, Canada.
authors.forename: Arthur
authors.initials: A
authors.lastname: Brown
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki FI-00014, Finland. emmy.verschuren@helsinki.fi.
authors.forename: Emmy W
authors.initials: EW
authors.lastname: Verschuren
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008168:Lung / Q000196:embryology / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D036121:Receptor, EphA3 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C491717:Epha3 protein, mouse; D036121:Receptor, EphA3; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Adenocarcinoma; EPH receptor A3; EPHA3; GEMM; Lung morphogenesis