Biology subjects

Hogg, K.

Publications and source records attributed to Hogg, K..

7 recordsLinked to original sources

bioRxiv2026

A scalable in vitro cell competition model identifies preleukemic super competitor clones

Preleukemic and leukemic conditions are frequently characterized by the acquisition of recurrent genetic mutations in hematopoietic stem cells (HSCs). One of the most frequently mutated genes in both clonal hematopoiesis and myeloid malignancies is the ten-eleven translocation 2 (TET2) gene, which encodes an epigenetic enzyme with a critical role in the regulation of gene transcription. While substantial work has shown that TET2 loss-of-function mutations lead to a clonal advantage, the underpinning cellular mechanism remains unclear, especially with respect to the early interactions with other cells. To study these early cell interactions of mutant and non-mutant cells, we developed an in vitro clonal competition platform where single-cell derived cultures are split into subclonal fractions which can be simultaneously cross-competed against multiple different clones of an opposing genotype. We identify a novel preleukemic cell phenotype that parallels the developmental biology phenomenon of super-competition, whereby ~10% of TET2-mutant clones actively and selectively suppress wild type (WT) cell expansion and, in some cases, completely eliminate WT clones. Molecular profiling and functional assays point to RAC1-GEF signalling inhibition as a specific WT cell vulnerability that is promoted, and tolerated, by neighbouring TET2-mutated clones. In addition to pinpointing selective drivers of non-mutant cell suppression, this clonal competition platform offers a broadly applicable new approach to study cell competition dynamics at an unprecedented scale.

cancer biology↗

bioRxiv2025

Bi-directional highways and super-seeder tissues underpin parasite dissemination in experimental visceral leishmaniasis.

Visceral leishmaniasis (VL) is a life-threatening parasitic disease caused by Leishmania donovani and L. infantum. Although VL is characterised by organ-specific immunopathology and parasitism of the spleen, liver and bone marrow, other tissues may harbour parasites without overt pathology. The mechanisms governing patterns of within-host dissemination and tissue tropism are largely unknown. We used a barcoded library of isogenic L. donovani and an ecological analysis framework to evaluate parasite population diversity across tissues and to map parasite dissemination in a murine infection model. We reveal an unexpected high degree of inter-connectivity between parasite populations demonstrating: i) continual bi-directional dissemination between viscera and skin; ii) the existence of "super-seeder" sites that act as hubs fuelling systemic spread; and iii) rerouting of dissemination "highways" following immune perturbation. These findings change our understanding of L. donovani pathogenesis, providing critical insights into infection dynamics with direct implications for relapse, treatment failure and transmission.

microbiology↗

bioRxiv2025

Characterising cancer-stroma interactions through high-content phenotyping from microscopy time-lapses

Understanding how cancer-stromal interactions shape cancer progression requires tools that can capture dynamic phenotypic changes in physiologically relevant conditions. Traditional approaches for studying co-culture interactions, such as transcriptomics and flow cytometry, provide valuable insights but are limited by their static nature and reliance on fixed or dissociated cells. In contrast, label-free time-lapse microscopy preserves temporal and spatial context, enabling observation of live-cell behaviours over time. A major challenge, however, lies in the analysis of the resulting high-dimensional datasets. Using co-cultures of breast cancer cells and cancer-associated fibroblasts (CAFs) as a model system, we show that the CellPhe toolkit enables label-free identification and phenotypic characterisation of different cell types within complex live-cell imaging datasets. Our analysis shows that exposure to CAFs drives marked phenotypic shifts in breast cancer cells, including elongation, loss of cell-cell adhesion, and redistribution of intracellular components - hallmarks of epithelial-mesenchymal transition (EMT). To probe the underlying mechanisms, we performed a Luminex immunoassay on CAF-conditioned media and identified secreted analytes strongly associated with EMT induction. Together, these results highlight how automated phenotyping can be integrated with molecular profiling to identify and characterise cellular processes shaped by stromal interactions and reveal the signalling mediators that drive them.

cancer biology↗

bioRxiv2025

Assembly and annotation of Solanum dulcamara and Solanum nigrum plant genomes, two nightshades with different susceptibilities to Ralstonia solanacearum

To understand why close wild plant relatives of crops, such as Solanum dulcamara, are resistant to Ralstonia solanacearum we need genetic resources to perform comparative studies and identify key genes and pathways. We de-novo assembled and annotated the genome of resistant S. dulcamara and susceptible Solanum nigrum plants using a hybrid approach including Oxford Nanopore Technologies and Illumina sequencing. Comparative genomic analysis was then performed to find differences between the genome of S. dulcamara and other susceptible Solanaceous species including potato, tomato, aubergine, and S. nigrum and one susceptible and one resistant S. americanum accession. We identified genes associated with auxin-transport only in S. dulcamara and a collection of pattern recognition receptors (PRRs) was identified in orthogroups only found in plant species with resistant/tolerant phenotype, suggesting novel plant receptors in these accessions that may improve recognition of pathogen-associated molecular patterns (PAMPs) associated with R. solanacearum. We also identified differences in methylation frequency across the gene bodies in both species, which may be associated with epigenetic regulation of resistance. Future work should assess the functional role of these PRRs during bacterial wilt development to determine if they could offer potential novel targets for breeding improved wilt resistance.

plant biology↗

bioRxiv2025

Spatial profiling of central nervous system cellular markers in murine breast cancer to brain metastases

BackgroundBrain metastasis occurs in approximately 16% of metastatic breast cancer patients, and incidence is increasing. Patients with breast cancer brain metastases frequently develop neurological problems including cognitive impairments and seizures. We previously demonstrated accumulation of activated microglia around the tumour site in a breast cancer brain metastasis model, which co-localised with spontaneously occurring local field potential events that resembled interictal epileptic discharges. However, the mechanisms underlying these spatially restricted effects on neuronal excitability are poorly understood. MethodsTo better understand the underlying cellular changes and potential mechanisms, we used digital spatial profiling of brain cell subtype-specific markers to chart the spatial organisation of neurons, oligodendrocytes, astrocytes, and microglia in relation to metastatic lesion site. We developed a novel chordline-based approach to analyse these spatial changes in biomarker distribution. ResultsSeveral protein markers associated with proliferation (Ki67), astrocytes (GFAP) and microglia (CD11b, IBA1, CD45, MSR1) were upregulated in the tumour compared to healthy contralateral brain parenchyma. In contrast, some neuroglial markers (MAP2, Neurofilament light, NeuN, S100B and TMEM119) were lower in the lesion compared to normal tissue. ConclusionsOverall, the protein marker changes in the lesion are indicative of neuronal cell loss and changes in the immune microenvironment of the metastatic lesion involving activated microglia, astrocytes and recruitment of peripheral immune cells. Such cellular changes may contribute to the changes in electrical activity resulting from brain metastases observed in mice and patients.

neuroscience↗

bioRxiv2021

The Rpd3-complex regulates expression of multiple cell surface recycling factors in yeast

Intracellular trafficking pathways control residency and bioactivity of integral membrane proteins at the cell surface. Upon internalisation, surface cargo proteins can be delivered back to the plasma membrane via endosomal recycling pathways. Recycling is thought to be controlled at the metabolic and transcriptional level, but such mechanisms are not fully understood. In yeast, recycling of surface proteins can be triggered by cargo deubiquitination and a series of molecular factors have been implicated in this trafficking. In this study, we follow up on the observation that many subunits of the Rpd3 lysine deacetylase complex are required for recycling. We validate ten Rpd3-complex subunits in recycling using two distinct assays and developed tools to quantify both. Fluorescently labelled Rpd3 localises to the nucleus and complements recycling defects, which we hypothesised were mediated by modulated expression of Rpd3 target gene(s). Bioinformatics implicated 32 candidates that function downstream of Rpd3, which were over-expressed and assessed for capacity to suppress recycling defects of rpd3{Delta} cells. This effort yielded 3 hits: Sit4, Dit1 and Ldb7, which were validated with a lipid dye recycling assay. Additionally, the essential phosphatidylinositol-4-kinase Pik1 was shown to have a role in recycling. We propose recycling is governed by Rpd3 at the transcriptional level via multiple downstream target genes.

cell biology↗

bioRxiv2021

Phospholipases D1 and D2 regulate cell cycling in primary prostate cancer cells and are differentially associated with the nuclear matrix

Phospholipases D1 and D2 (PLD1/2) have been implicated in tumorigenesis. We previously detected higher expression of PLD in the nuclei of patient-derived prostate cancer (PCa) cells and prostate cancer cell lines. Here we have examined whether PLD1 or PLD2 are associated with the nuclear matrix and influence cell cycling. PLD1/PLD2 were detected by qualitative immunofluorescence in cultured PCa cells and extracted with a standardised protocol to reveal nuclear matrix-associated proteins. The effects of isoform-specific inhibition of PLD1or PLD2 on PCa cell cycle progression were analysed by flow cytometry. PLD2 mainly co-localised with the nucleolar marker fibrillarin in PCa cells. However, even after complete extraction, some PLD2 remained associated with the nuclear matrix. Inhibiting PLD2 effectively reduced PCa cell cycling into and through S phase. In contrast, PLD1 inhibition effects were weaker, and a subpopulation of cycling patient-derived PCa cells was unaffected by PLD1 inhibition. When associated with the nuclear matrix PLD2 could generate phosphatidic acid to regulate nuclear mTOR and control downstream transcriptional events. The association of PLD2 with the nucleolus also implies a role in stress regulation. The cell cycling results highlight the importance of PLD2 inhibition as a novel potential prostate cancer therapeutic mechanism by differential regulation of cell proliferation.

cancer biology↗