SOX2 drives bronchial dysplasia in a novel organotypic model of early human squamous lung cancer

Lúcia L. Correia, Jo Anne Johnson, Peter McErlean, Julien Bauer, Hassan Farah, Doris M. Rassl, Robert C. Rintoul, Tariq Sethi, Paul Lavender, Emma L. Rawlins, Trevor D. Littlewood, Gerard I. Evan, Frank M. McCaughan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


Rationale: 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. Objectives: (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. Methods: 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. Measurements and Main Results: 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 ofAKT prevents the initiation of the dysplastic phenotype. Conclusions: 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.

Original languageEnglish
Pages (from-to)1494-1508
Number of pages15
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number11
Publication statusPublished - 1 Jun 2017


  • Bronchial dysplasia
  • Early lung cancer
  • Organotypic culture
  • Sex-determining region Y-box 2 (SOX2)
  • Squamous lung cancer


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