Biology subjects

Ogden, J.

Publications and source records attributed to Ogden, J..

4 recordsLinked to original sources

bioRxiv2026

In vivo cellular localisation and nanoscale organisation of NLRP3 inflammasomes

The NLRP3 inflammasome is a critical regulator of inflammation, yet the localisation, organisation, and cellular sources of endogenous NLRP3 inflammasomes remain incompletely understood. Here, we generated NLRP3-mScarlet-I endogenous reporter mice enabling visualisation of NLRP3 at physiological levels in primary cells and in vivo. We show that activated NLRP3 associated with PI4P-positive membranes from multiple organelles, supporting a model where diverse membrane platforms act as a scaffold to nucleate inflammasome assembly. Super-resolution imaging revealed that NLRP3 and ASC occupy distinct nanoscale architectures within the inflammasome, with NLRP3 displaying marked structural heterogeneity and stimulus-dependent organisation. Unexpectedly, circulating monocytes and neutrophils, rather than tissue-resident populations, emerged as the dominant NLRP3-expressing cells in vivo which rapidly infiltrated tissues following systemic inflammation, highlighting an underappreciated cellular source of rapid inflammasome-driven responses. These findings reveal previously unrecognised insights into inflammasome organisation and localisation, establishing a powerful resource for investigating endogenous NLRP3 biology in health and disease.

immunology↗

bioRxiv2025

Studying a human genetic model of lung squamous cell carcinoma with organotypic cultures and xenografts uncovers distinct advantages of each system and implicates NOTCH1 loss in tumour development

Selecting appropriate experimental systems is crucial in cancer research, where factors such as model relevance, cost, and resource availability guide decisions. A detailed understanding of the strengths and limitations of each model helps ensure their optimal use. We recently developed a human lung squamous cell carcinoma (LUSC) model using genetically engineered human bronchial epithelial cells (hBECs). These were studied through organotypic air-liquid interface (ALI) cultures and standard in vitro assays, including proliferation, invasion, and anchorage-independent growth. However, we did not evaluate whether the same mutant hBECs behaved similarly in vivo, or if in vivo models offered distinct advantages. To address this, we conducted a comparative phenotypic analysis of mutant hBECs derived from the same donor in both ALI cultures and xenografts in immunocompromised mice. Both models followed a similar oncogenic trajectory, involving squamous differentiation and activation of Nrf2 and PI3K/Akt pathways, characteristic of the classical LUSC subtype. However, some transcriptomic differences related to an increase in microtubule formation and cell motility in xenografts emerged. Additionally, xenograft gene expression profiles more closely matched classical LUSC tumours than ALI cultures. Importantly, we observed spontaneous squamous differentiation in the absence of SOX2 overexpression and detected selection for NOTCH1 mutations in specific in vivo mutants. Truncation of NOTCH1 promoted squamous differentiation and suppressed mucociliary features in ALI cultures, underscoring its role as a potential LUSC driver. In summary, mutant hBECs in vitro and in vivo showed largely consistent phenotypes, validating both systems. However, in vivo models can enable the unbiased discovery of new genetic LUSC driver genes. This highlights the complementary value of integrating both model types in LUSC research.

cancer biology↗

bioRxiv2023

A novel human model to deconvolve cell-intrinsic phenotypes of genetically dysregulated pathways in lung squamous cell carcinoma

Tractable, patient relevant models are needed to investigate cancer progression and heterogeneity. Here, we report an alternative and unique 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) was investigated by generating hBECs harbouring cumulative alterations. Our analyses confirmed 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 was consistent with the classical LUSC subtype. Importantly, we connected 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.

cancer biology↗

bioRxiv2022

Interrogating the Precancerous Evolution of Pathway Dysfunction in Lung Squamous Cell Carcinoma Using XTABLE

Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE, an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two and multiple group comparisons, interrogation of genes of interests and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.

bioinformatics↗