Biology subjects

Hogan, C.

Publications and source records attributed to Hogan, C..

10 recordsLinked to original sources

bioRxiv2026

Early Progression Cells mark a stem-like state associated with pancreatic cancer initiation and progression

Pancreatic cancer is deemed to progress from microscopic pancreatic intraepithelial neoplasia (PanINs). However, low grade PanINs are frequently detected in the general population without presentation or increased risk of developing cancer, suggesting that many PanINs never progress to tumours. What precisely characterises PanINs that develop into tumours is insufficiently understood. Using a mouse model where pancreatitis-induced tissue injury promotes pancreatic cancer from rare KrasG12D cells, we identify Early Progression Cells (EPCs) as a new entity, a novel population of cancer stem-like cells. Transcriptomic analyses illustrate EPCs as stress-adapted, inflammation responsive stem cells that also upregulate gene programmes indicative of microenvironment remodelling. Using identified EPC protein markers, we show that EPCs are prevalent in early metaplastic stages and in PanIN progression from low grade to high grade but are rarer in tumours. PanIN- and tumour-derived sphere and organoid assays demonstrate that EPCs possess all characteristics of stem cells in vitro and are dependent on Nupr1 stress response pathways for survival and growth. We identify APP-CD74 as a novel cell-cell interaction pathway between EPCs and neighbouring epithelial cells in PanINs and tumours. Inhibition of CD74 activity in vitro induces high-grade PanIN organoid death, suggesting EPCs are critical for high-grade PanINs. Using spatial transcriptomics of human samples, we detect gene signatures of EPCs in distinct regions of human PanIN and PDAC tissues, including APP-CD74 interactions, providing compelling evidence that EPCs are relevant to human disease. Further understanding of EPC biology will likely uncover new knowledge on why rare PanINs progress towards tumours.

cancer biology↗

bioRxiv2026

Targeted DUX4 base editing improves muscle function in an iPSC-derived model of childhood-onset FSHD

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common dominant muscular dystrophies and remains without an approved disease modifying therapy. Caused by the aberrant expression of the cytotoxic gene DUX4, FSHD is typically diagnosed in adulthood, however clinical onset in children (<18 years of age) is often associated with a more severe and rapid disease. While clinical trials are underway, a lack of human-specific pre-clinical models limit effective testing of potential therapies, particularly in children. To fill this gap, we describe here the development of induced pluripotent stem cell-derived 2-and 3-dimensional skeletal muscle models of children with clinically defined mild, moderate, and severe FSHD. These iPSC-derived muscle models replicate key features of FSHD, including aberrant DUX4 mRNA expression, muscle atrophy, and weakness, which correlate with the individuals specific disease severity. Next, we assessed the efficacy of adenine base editing (ABE) as a potential gene therapy approach to treat FSHD. DUX4-targeted ABE reduced DUX4 mRNA expression, improved muscle area and force generation in the most severe individual. Together this work supports the use of iPSC-derived skeletal muscle models as a less invasive method to study childhood-onset FSHD and establishes targeted DUX4 gene editing therapies as a potential treatment approach.

cell biology↗

bioRxiv2025

Viral infections shape inter-individual immune variability

Viral infections can shape adaptive immunity, but whether they also influence innate immune responses later in life remains incompletely characterized. Here, we profiled serum from 12 healthy adults using VirScan, a high-throughput serological assay that infers prior viral exposures by mapping antiviral antibody reactivity across a broad range of viral epitopes. We paired this with ex vivo stimulation of TLR3 and TLR7/8 antiviral pathways and tested whether post-stimulation inflammatory responses are associated with prior viral exposures. At the antibody level, we observed consistent immunodominance at the protein level across individuals, alongside substantial variability at the epitope level. At the functional level, prior exposure to HSV-1, HSV-2, and norovirus was associated with differential production of CCL4, MCP-2, and TNF following TLR7/8 stimulation, respectively. This pilot study establishes a framework for integrating broad viral serology with functional immune profiling to investigate links between lifetime exposures and immune variability. Our results suggest that past viral infections, including acute infections, can contribute to variation in innate immune responses later in life. Larger studies will be required to validate these associations, establish causality, and determine the underlying mechanisms.

immunology↗

bioRxiv2025

Renewable Self-Folding Origami Constructed from Bioengineered Bacterial Cellulose

This work presents the first genetically engineered cellulose actuator where the structural basis for actuation is directly encoded in the producing organisms DNA. By modifying Komagataeibacter rhaeticus to secrete BslA protein and treating with NaOH, we create surface-activated bacterial cellulose that exhibits water contact angles 2.4x greater than and water retention 8.2 x less than unmodified cellulose. Layering this hydrophobic BslA-activated cellulose with untreated bacterial cellulose produces a biofabricated actuator driven by differential strain during dehydration. The actuation follows the Timoshenko bilayer beam equation adapted for hydrogels and can be fabricated either by shaping mature pellicles or through direct growth in 3D-printed autoclavable molds. We demonstrate two applications with a self-folding bacterial cellulose origami crane and a biomimetic bacterial cellulose gripper capable of supporting more than 360 times its own weight. This approach represents a significant advance in sustainable soft robotics through the creation of fully renewable, biodegradable, and genetically programmable actuators.

synthetic biology↗

bioRxiv2024

ACSS2 contributes to transcriptional regulation in Cajal-Retzius cells in a mouse model of Alzheimer's disease

Dysregulation of histone acetylation in the brain has emerged as a major contributor to human Alzheimers disease (AD). The mechanisms by which these protective or risk-conferring epigenetic marks are established and maintained are under intense investigation. ACSS2 (Acetyl-CoA Synthetase 2) is a key metabolic enzyme that is chromatin-associated in neurons. ACSS2 is recruited to specific promoters and generates a local pool of acetyl-CoA from acetate, thereby fueling histone acetylation and driving the expression of neuronal genes that regulate learning and memory. Here, we examine the contribution of ACSS2-mediated histone acetylation to AD-related molecular and behavioral outcomes. Using a mouse model of human pathological AD-Tau injection, we show that loss of ACSS2 exacerbates Tau-related memory impairments, while dietary supplementation of acetate rescues learning in an ACSS2-dependent manner. Combining state-of-the-art proteomic and genomic approaches, we demonstrate that this effect is accompanied by ACSS2-dependent incorporation of acetate into hippocampal histone acetylation, which facilitates gene expression programs related to learning. Further, we identify Cajal-Retzius neurons as a critical hippocampal neuronal population affected, exhibiting the largest epigenetic and transcriptional dysregulation. Overall, these results reveal ACSS2 as a key neuroprotective metabolic enzyme, dysregulation of which might play an important role in the etiology of human AD, and guide the development of future therapies for AD and related dementia.

neuroscience↗

bioRxiv2024

ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

Epigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with a role in neuronal function in Alzheimers disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and postmitotic state. ACSS2 can be recruited to the nucleus and chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function. SummaryACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.

neuroscience↗

bioRxiv2024

Oncogenic KRAS cells use Wnt signalling and cell dormancy to override homeostatic cell elimination mechanisms in adult pancreas.

Epithelial tissues use homeostatic defence mechanisms to actively expel aberrant or genetically mutant cells and prevent disease. When present in healthy tissues in low numbers, we show that cells expressing cancer-causing mutations (KrasG12D, p53R172H) compete with normal cells for survival and are often eliminated. Thus, tumour initiation must require mechanisms whereby mutant cells override tissue defence mechanisms to remain in a tissue; however, the biology of these initial events is poorly understood. Here, we use an in vivo model of sporadic tumorigenesis in the adult pancreas to show that a population of KrasG12D- or p53R172H-expressing cells are never eliminated from the epithelium. Using RNA sequencing of non-eliminated populations and quantitative fluorescence imaging, we show that {beta}-catenin-independent Wnt5a signalling, and cell dormancy are key features of surviving KrasG12D cells in vivo. We demonstrate that Wnt5a (and not Wnt3a) inhibits apical extrusion of RasV12 cells in vitro by promoting stable E-cadherin-based cell-cell adhesions at RasV12-normal cell-cell boundaries. Inhibition of Wnt5a signalling restores E-cadherin dynamics at normal-mutant boundaries and apical extrusion in vitro. RasV12 cells arrested in the cell cycle are not extruded and this is rescued when Wnt signalling is inhibited. In the pancreas, Wnt signalling, E-cadherin and {beta}-catenin are increased at cell-cell contacts between non-eliminated KrasG12D cells and normal neighbours. Importantly, we demonstrate that active Wnt signalling is a general mechanism required to promote KrasG12D and p53R172H cell survival in vivo. Treatment with porcupine inhibitor rescues pancreas tissue defence by switching mutant cell retention to cell expulsion. Our results suggest that RAS mutant cells activate Wnt and a dormant cell state to avoid cell expulsion and to survive in the adult pancreas.

cell biology↗

bioRxiv2023

Decreased voluntary alcohol intake and ventral striatal epigenetic and transcriptional remodeling in male Acss2 KO mice

Metabolic-epigenetic interactions are emerging as key pathways in regulating alcohol-related transcriptional changes in the brain. We previously demonstrated that this is mediated by the metabolic enzyme Acetyl-CoA synthetase 2 (Acss2), which is nuclear and chromatin-bound in neurons. Mice lacking Acss2 fail to deposit alcohol-derived acetate onto histones in the brain and show no conditioned place preference for ethanol reward. Here, we explored the role of this pathway during voluntary alcohol intake. We found that Acss2 KO mice consumed significantly less alcohol during drinking-in-the-dark, and this effect was primarily driven by males. We performed genome-wide transcriptional profiling of 7 key brain regions implicated in alcohol and drug use, and found that, following drinking, Acss2 KO mice exhibited blunted gene expression in the ventral striatum, and similar to the behavioral differences, transcriptional dysregulation was more pronounced in male mice. Further, we found that the gene expression changes were associated with depletion of ventral striatal histone acetylation (H3K27ac) in Acss2 KO mice compared to WT. Taken together, our data suggest that Acss2 plays an important role in orchestrating ventral striatal epigenetic and transcriptional changes during voluntary alcohol drinking, especially in males. Consequently, targeting this pathway could be a promising new therapeutic avenue.

neuroscience↗

bioRxiv2020

Canonical Wnt signalling is activated during BEC-to-hepatocyte conversion in vivo and modulates liver epithelial cell plasticity in hepatic organoids

While it is recognized that the Wnt/{beta}-catenin pathway orchestrates hepatocyte proliferation in both homeostasis and injury, little is known about the importance of {beta}-catenin in biliary epithelial cell (BEC) plasticity. In this study, the dynamics of activation of the canonical Wnt pathway were investigated during BEC-to-hepatocyte conversion using as a model methionine/choline deficient (MCD)-injured livers where hepatocyte proliferation was compromised by the overexpression of p21. In this model, activation of {beta}-catenin was found an event associated with BEC reprogramming. Using ductal organoids to model BECs transitioning into hepatocytes, we found that activation of the Wnt/{beta}-catenin pathway in these cells promoted partial escape from a biliary fate and triggered the acquisition of progenitor cell features. Our data furthermore support that BECs are source of Wnt ligands and that Rspo proteins potentially act as the limiting factor controlling the activation of {beta}-catenin activation and BEC reprogramming during severe liver damage.

cell biology↗

bioRxiv2020

KRASG12D mutant cells are outcompeted by wild type neighbours in adult pancreas in an EPHA2-dependent manner.

As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbours for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that prior to being cleared, KrasG12D cells lose cell volume, segregate from normal cells and decrease E-cadherin-based cell-cell adhesions with normal neighbours. We identify EphA2 receptor is an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells no longer segregate, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. Retention of KRasG12D cells leads to an increased burden of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumour suppressor in pancreatic cancer.

cell biology↗