title: SOX2 Drives Bronchial Dysplasia in a Novel Organotypic Model of Early Human Squamous Lung Cancer.
abstract: Improving the early detection and chemoprevention of lung cancer are key to improving outcomes. The pathobiology of early squamous lung cancer is poorly understood. We have shown that amplification of sex-determining region Y-box 2 (SOX2) is an early and consistent event in the pathogenesis of this disease, but its functional oncogenic potential remains uncertain. We tested the impact of deregulated SOX2 expression in a novel organotypic system that recreates the molecular and microenvironmental context in which squamous carcinogenesis occurs.
  
  
  
  (1) To develop an in vitro model of bronchial dysplasia that recapitulates key molecular and phenotypic characteristics of the human disease; (2) to test the hypothesis that SOX2 deregulation is a key early event in the pathogenesis of bronchial dysplasia; and (3) to use the model for studies on pathogenesis and chemoprevention.
  
  
  
  We engineered the inducible activation of oncogenes in immortalized bronchial epithelial cells. We used three-dimensional tissue culture to build an organotypic model of bronchial dysplasia.
  
  
  
  We recapitulated human bronchial dysplasia in vitro. SOX2 deregulation drives dysplasia, and loss of tumor promoter 53 is a cooperating genetic event that potentiates the dysplastic phenotype. Deregulated SOX2 alters critical genes implicated in hallmarks of cancer progression. Targeted inhibition of AKT prevents the initiation of the dysplastic phenotype.
  
  
  
  In the appropriate genetic and microenvironmental context, acute deregulation of SOX2 drives bronchial dysplasia. This confirms its oncogenic potential in human cells and affords novel insights into the impact of SOX2 deregulation. This model can be used to test therapeutic agents aimed at chemoprevention.
authors.affiliation: 1 Department of Biochemistry.
authors.forename: Lúcia L
authors.initials: LL
authors.lastname: Correia
authors.affiliation: 2 Wellcome Trust/Cancer Research UK Gurdon Institute.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: 3 Department of Asthma, Allergy, and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; and.
authors.forename: Peter
authors.initials: P
authors.lastname: McErlean
authors.affiliation: 4 Cambridge Genomic Services, Department of Pathology, and.
authors.forename: Julien
authors.initials: J
authors.lastname: Bauer
authors.affiliation: 3 Department of Asthma, Allergy, and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; and.
authors.forename: Hassan
authors.initials: H
authors.lastname: Farah
authors.affiliation: 5 Department of Pathology and.
authors.forename: Doris M
authors.initials: DM
authors.lastname: Rassl
authors.affiliation: 6 Department of Thoracic Oncology, Papworth Hospital Foundation National Health Service Trust, Papworth Everard, Cambridge, United Kingdom.
authors.forename: Robert C
authors.identifier: 0000-0003-3875-3780
authors.initials: RC
authors.lastname: Rintoul
authors.affiliation: 3 Department of Asthma, Allergy, and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; and.
authors.forename: Tariq
authors.initials: T
authors.lastname: Sethi
authors.affiliation: 3 Department of Asthma, Allergy, and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Lavender
authors.affiliation: 2 Wellcome Trust/Cancer Research UK Gurdon Institute.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Rawlins
authors.affiliation: 1 Department of Biochemistry.
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Littlewood
authors.affiliation: 1 Department of Biochemistry.
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.affiliation: 1 Department of Biochemistry.|7 Department of Medicine, University of Cambridge, Cambridge, United Kingdom.|3 Department of Asthma, Allergy, and Lung Biology, Guy's Hospital, King's College London, London, United Kingdom; and.
authors.forename: Frank M
authors.identifier: 0000-0003-3969-0822
authors.initials: FM
authors.lastname: McCaughan
mesh_terms: D001997:Bronchopulmonary Dysplasia / Q000235:genetics* / Q000503:physiopathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000503:physiopathology*; D018929:Cell Culture Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D008954:Models, Biological; D055748:SOXB1 Transcription Factors / Q000235:genetics*
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
keywords: bronchial dysplasia; early lung cancer; organotypic culture; sex-determining region Y-box 2 (SOX2); squamous lung cancer