Biology subjects

Finnie, J.

Publications and source records attributed to Finnie, J..

5 recordsLinked to original sources

bioRxiv2025

Genetic Ablation and Multi-Omics Profiling Reveal CEP55 as a Key Driver of Tumorigenesis in Diverse Cancer Models

BackgroundCEP55 is a centrosomal protein with emerging oncogenic roles. It is overexpressed in many cancers, where it drives genomic instability, phenocopies PTEN loss and hyperactivates the PI3K/AKT pathway, thereby promoting aggressive and therapy-resistant tumors. MethodsWe developed an inducible Cep55 knockout (KO) mouse model as well as generated primary, immortalized (SV40), and transformed (E1A/Ras) mouse embryonic fibroblasts (MEFs) for functional and proteomic assays. Tumorigenesis was studied using E1A/Ras MEF transplantation and a Pten-deficient genetically engineered mouse model (GEMM). Multi-omics apparatus including proteomics, and spatial transcriptomics, histopathology, immunobloting and functional assays were employed to elucidate underlying mechanisms. Findings were cross-validated using human cancer datasets. ResultsCep55 ablation remodeled the extracellular matrix (ECM), disrupted integrin and oncogenic signaling, reduced AKT/ERK activation, and induced stress pathways. Cep55 knockouts (KO) cells showed impaired proliferation, migration, invasion, and adhesion. In vivo, unlike the embryonic lethality observed in constitutive KOs, the inducible Cep55 deletion was well-tolerated in adult mice. Strikingly, tumors derived from Cep55-null EIA/RAS-transformed MEFs exhibited delayed onset and progression. In the genetically engineered cancer-prone mouse model, Cep55 deletion on a Pten-deficient background led to a greater than seven-fold increase in median survival. Spatial transcriptomics on cancerous tissues revealed that CEP55 regulates ECM remodeling, integrin expression, trafficking, and cell adhesion, supporting its critical role in tumor progression to metastasis. ConclusionCEP55 is dispensable for adult homeostasis but essential for tumorigenesis, especially with PTEN loss. Its deletion suppresses transformation, delays tumor growth, and prolongs survival, supporting CEP55 as a therapeutic target in PTEN-deficient cancers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/685219v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@3d81e8org.highwire.dtl.DTLVardef@1bd5a7org.highwire.dtl.DTLVardef@167ecf3org.highwire.dtl.DTLVardef@1f57b95_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

A longitudinal evaluation of localised chronic Pseudomonas aeruginosa infection in cystic fibrosis rat models

Recurrent bacterial infections with Pseudomonas aeruginosa result in chronic airway inflammation, lung damage and eventual respiratory failure, and are the major cause of morbidity and mortality in people with cystic fibrosis (CF). Animal models are essential for understanding disease progression and assessing potential treatments in the presence of infection. Previously reported P. aeruginosa lung infection rodent models for CF research have some weakness, including acute infection rather than chronic, associated mortality, use of laboratory strains of P. aeruginosa and the use of non-CF rodents. The aim of this study was to create a localised P. aeruginosa infection in wildtype and two CF rat models, by delivering bacteria embedded agar beads using a miniature bronchoscope. The resulting infection was well tolerated by all animals of all genotypes with no mortality associated with the procedure or infection. Histologically the affected regions were localised to the right lung, with bronchopneumonia present. Bacteria persisted for 9 weeks (63 days) in all genotypes, with lung function changes observed by day 63 of the infection.

pathology↗

bioRxiv2023

Staphylococcus aureus biofilm secreted factors cause mucosal damage, mast cell infiltration and goblet cell hyperplasia in a rat rhinosinusitis model

Chronic Rhinosinusitis (CRS) is an inflammatory condition of the paranasal sinus mucosa. Despite being a common health issue, the exact cause of CRS is yet to be understood. However, research suggests that Staphylococcus aureus, particularly in the biofilm form, drives the disease. This study aimed to investigate the impact of long-term exposure to secreted factors of Staphylococcus aureus biofilm (SABSF), harvested from clinical isolates of non-CRS carriers and CRS patients, on the nasal mucosa in a rat model. Wistar rats were randomised (n=5/group) to receive daily intranasal instillations of 40 L (200 g/L) SABSF for 28 days or vehicle control with S. aureus isolated from the sinuses of a non-CRS carrier, a type 2 endotype CRS with nasal polyps (CRSwNP) patient, and a non-type 2 endotype CRS without nasal polyps (CRSsNP) patient. The sinonasal samples of the rats were then analysed through histopathology and transcriptome profiling. The results showed that all three intervention groups displayed significant lymphocytic infiltration (p[≤]0.05). However, only the SABSF collected from the CRSwNP patient caused significant mucosal damage, mast cell infiltration, and goblet cell hyperplasia compared to the control. The transcriptomics results indicated that SABSF significantly enriched multiple inflammatory pathways and showed distinct transcriptional expression differences between the control group and the SABSF collected from CRS patients (p[≤]0.05). Additionally, the SABSF challenges induced the expression of IgA and IgG but not IgE. In conclusion, this in vivo study indicates that long-term exposure to SABSF leads to an inflammatory response in the nasal mucosa with increased severity for S. aureus isolated from a CRSwNP patient. The findings of this study shed light on the role of S. aureus in the development of CRS and could inform future research and treatment efforts.

immunology↗

bioRxiv2022

Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice

B-Crystallin is a heat shock chaperone protein which binds to misfolded proteins to prevent their aggregation. It is overexpressed in a wide-variety of cancers. Previous studies using human cancer cell lines and human xenograft models have reported tumor suppressor or tumor promoter (oncogene) roles for B-Crystallin depending on cellular context and environmental conditions. To determine the causal relationship between CRYAB overexpression and cancer, we generated a Cryab overexpression knock-in mouse model. This model revealed that constitutive overexpression of Cryab results in the formation of a variety of lethal spontaneous primary and metastatic tumors in mice. In vivo, the overexpression of Cryab correlated with the upregulation of epithelial-to-mesenchymal (EMT) markers, angiogenesis and some oncogenic proteins including Basigin. In vitro, using E1A/Ras transformed mouse embryonic fibroblasts (MEFs), we observed that the overexpression of Cryab led to the promotion of cell survival via upregulation of Akt signaling and downregulation of pro-apoptotic pathway mediator JNK, with subsequent attenuation of apoptosis as assessed by cleaved caspase-3. Overall, through the generation and characterization of Cryab overexpression model, we provide evidence supporting the role of B-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis.

cancer biology↗

bioRxiv2021

Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis

Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a critical regulator of cytokinesis predominantly in transformed cells and its deregulation is linked to carcinogenesis. However, its molecular functions during embryonic development in mammals have not been clearly defined. We have generated a Cep55 knockout (Cep55-/-) mouse model which demonstrated perinatal lethality associated with a wide range of neural defects. Focusing our analysis on the neocortex, we show that Cep55-/- embryos exhibited depleted neural stem/progenitor cells in the ventricular zone as a result of significantly increased cellular apoptosis. Mechanistically, we demonstrated that Cep55-loss downregulates the pGsk3{beta}/{beta}-Catenin/Myc axis in an Akt-dependent manner. The phenotype was recapitulated using human cerebral organoids and we could rescue the phenotype by inhibiting active Gsk3{beta}. Additionally, we show that Cep55-loss leads to a significant reduction of ciliated cells, highlighting its novel role in regulating ciliogenesis. Collectively, our findings demonstrate a critical role of Cep55 during brain development and provide mechanistic insights that may have important implications for genetic syndromes associated with Cep55-loss.

cell biology↗