A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma

Julia Ogden, Robert Sellers, Sudhakar Sahoo, Anthony Oojageer, Anshuman Chaturvedi, Caroline Dive and Carlos Lopez-Garcia ()
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Julia Ogden: Wilmslow Road
Robert Sellers: Wilmslow Road
Sudhakar Sahoo: Wilmslow Road
Anthony Oojageer: Wilmslow Road
Anshuman Chaturvedi: Wilmslow Road
Caroline Dive: Wilmslow Road
Carlos Lopez-Garcia: Wilmslow Road

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Tractable, patient-relevant models are needed to investigate cancer progression and heterogeneity. Here, we report an alternative in vitro model of lung squamous cell carcinoma (LUSC) using primary human bronchial epithelial cells (hBECs) from three healthy donors. The co-operation of ubiquitous alterations (TP53 and CDKN2A loss) and components of commonly deregulated pathways including squamous differentiation (SOX2), PI3K signalling (PTEN) and the oxidative stress response (KEAP1) is investigated by generating hBECs harbouring cumulative alterations. Our analyses confirms that SOX2-overexpression initiates early preinvasive LUSC stages, and co-operation with the oxidative stress response and PI3K pathways to drive more aggressive phenotypes, with expansion of cells expressing LUSC biomarkers and invasive properties. This cooperation is consistent with the classical LUSC subtype. Importantly, we connect pathway dysregulation with gene expression changes associated with cell-intrinsic processes and immunomodulation. Our approach constitutes a powerful system to model LUSC and unravel genotype-phenotype causations of clinical relevance.

Date: 2025
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DOI: 10.1038/s41467-025-58343-y

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