A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma
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 ubiqu...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58343-y |
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| author | Julia Ogden Robert Sellers Sudhakar Sahoo Anthony Oojageer Anshuman Chaturvedi Caroline Dive Carlos Lopez-Garcia |
| author_facet | Julia Ogden Robert Sellers Sudhakar Sahoo Anthony Oojageer Anshuman Chaturvedi Caroline Dive Carlos Lopez-Garcia |
| author_sort | Julia Ogden |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-324750c9b05d4fda8a7667c610e87fe9 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-324750c9b05d4fda8a7667c610e87fe92025-08-20T02:08:09ZengNature PortfolioNature Communications2041-17232025-04-0116111710.1038/s41467-025-58343-yA human model to deconvolve genotype-phenotype causations in lung squamous cell carcinomaJulia Ogden0Robert Sellers1Sudhakar Sahoo2Anthony Oojageer3Anshuman Chaturvedi4Caroline Dive5Carlos Lopez-Garcia6Cancer Research UK Manchester Institute, Wilmslow RoadCancer Research UK Manchester Institute, Wilmslow RoadCancer Research UK Manchester Institute, Wilmslow RoadCancer Research UK Manchester Institute, Wilmslow RoadDepartment of Histopathology, The Christie Hospital, Wilmslow RoadCancer Research UK Manchester Institute, Wilmslow RoadCancer Research UK Manchester Institute, Wilmslow RoadAbstract 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.https://doi.org/10.1038/s41467-025-58343-y |
| spellingShingle | Julia Ogden Robert Sellers Sudhakar Sahoo Anthony Oojageer Anshuman Chaturvedi Caroline Dive Carlos Lopez-Garcia A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma Nature Communications |
| title | A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma |
| title_full | A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma |
| title_fullStr | A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma |
| title_full_unstemmed | A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma |
| title_short | A human model to deconvolve genotype-phenotype causations in lung squamous cell carcinoma |
| title_sort | human model to deconvolve genotype phenotype causations in lung squamous cell carcinoma |
| url | https://doi.org/10.1038/s41467-025-58343-y |
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