Biology subjects

Cox, A. G.

Publications and source records attributed to Cox, A. G..

7 recordsLinked to original sources

bioRxiv2026

Cholesterol remodels the endoplasmic reticulum to control myofibroblastic CAF function

Chronic exposure of local fibroblasts to the reactive tumour niche results in the emergence of cancer-associated fibroblasts (CAFs), which can be classed into multiple subtypes with distinct functional and molecular characteristics. Of these subtypes, myofibroblastic CAFs (myCAFs), contribute to tumour progression primarily by depositing and remodelling extracellular matrix (ECM) within the tumour microenvironment (TME). ECM production is known to be a metabolically demanding process, but specific metabolic pathways that are reprogrammed during myCAF activation are poorly understood. Here, we show that cholesterol biosynthesis is elevated in myCAFs relative to normal fibroblasts. We find that cholesterol is specifically enriched in the myCAF endoplasmic reticulum (ER) membrane and is associated with augmented ER mass and enhanced ER secretory function. Importantly, we demonstrate that pharmacological or genetic inhibition of cholesterol biosynthesis plays a critical role in regulating the ECM-secreting and ECM remodelling function of myCAFs. Moreover, we show that inhibition of cholesterol biosynthesis in myCAFs markedly constrains mammary tumour metastasis in vivo. These studies suggest that cholesterol biosynthesis represents a metabolic vulnerability that can be exploited to normalise myCAF-mediated ECM dysfunction in the TME.

cell biology↗

bioRxiv2026

NRF2 co-opts the SWI/SNF complex to drive liver cell plasticity

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a role in the regulation of redox homeostasis and cellular metabolism. Activating mutations in the NRF2 pathway have been identified in approximately 15% of liver cancer patients. However, the mechanisms by which NRF2 promotes liver tumorigenesis are poorly understood. Employing a transgenic zebrafish model with hepatocyte-specific, inducible expression of a clinically relevant constitutively active NRF2 mutant (NRF2T80K), we show that constitutive activation of NRF2 drives hepatocyte to cholangiocyte transdifferentiation. Importantly, we demonstrate that NRF2 affects liver cell plasticity in a cell-autonomous, evolutionarily conserved, and reversible manner. Utilizing an epigenetic-focused chemical screen, the BRG1/BRM inhibitor FHD-286 was identified as a potent suppressor of NRF2-driven transdifferentiation. Overall, our study reveals a novel role for NRF2 in the regulation of liver cell plasticity during tumour initiation and identifies a therapeutic approach to overcome the oncogenic activity of NRF2.

cancer biology↗

bioRxiv2026

YAP disrupts bile acid homeostasis to drive cancer-associated cachexia

Cancer-associated cachexia is a severe metabolic syndrome marked by dramatic loss of adipose and muscle mass. Although preclinical models have advanced our understanding of cachexia, there are still no approved therapies due to the limited insights into the mechanisms underlying tissue wasting. Here, we utilise a YAP-driven model of liver cancer in zebrafish, which rapidly develops cachexia, to uncover an evolutionarily conserved role for bile acid disruption in the onset of cachexia. Spatial transcriptomic analysis revealed that YAP induces a bi-lineage cholangiocarcinoma phenotype, which was associated with bile acid dysregulation. Mechanistically, we establish that both bile acid synthesis (via CYP7A1) and signalling through the bile acid receptor TGR5 are essential for cachexia induction. Notably, we find that the promotion of bile acid excretion with odevixibat ameliorates cachexia. Together, our findings reveal an evolutionarily conserved mechanism by which YAP promotes cachexia and suggest a potential therapeutic strategy to treat the syndrome.

cancer biology↗

bioRxiv2025

A spatially localised cryoinjury model to study liver regeneration in zebrafish

This Protocol Extension describes adapting an existing cryoinjury protocol to study heart regeneration in zebrafish1. We recently characterized a novel hepatic cryoinjury model that induces localized necrosis, inflammation, and fibrosis, which resolves as the liver regenerates. Here, we present a detailed description of the hepatic cryoinjury procedure. One of the key advantages of this model is that it allows direct comparison of healthy and injured liver parenchyma within individual animals. Our hepatic cryoinjury model provides a rapid and reproducible platform to investigate the molecular and cellular mechanisms underlying fibrosis and liver regeneration. This Protocol Extension aims to extend the reach of the cryoinjury approach for deployment in studying liver regeneration.

cell biology↗

bioRxiv2025

A Multi-omic approach reveals iron availability influences hepatocyte cell fate

Recent evidence has highlighted the importance of employing culture media designed to emulate the metabolic environment Here, we utilize the physiological medium Plasmax to examine the impact of nutrient availability on the human hepatocyte cell line, HepG2. Incubation of HepG2 cells in Plasmax suppressed a transcriptional program driven by Hepatocyte Nuclear Factor 4 (HNF4A), a master regulator of hepatocyte identity. Given that HepG2 cells were originally isolated from a patient with hepatoblastoma, this suggests reversion to the native state in physiological media. Importantly, exclusion of iron from Plasmax reinstated the HNF4A-driven transcriptional program. These studies suggest a relationship between iron availability and the fidelity of hepatocyte cell fate and highlight the importance of more faithfully recapitulating in vivo metabolite availability in vitro.

cell biology↗

bioRxiv2023

Development of a hepatic cryoinjury model to study liver regeneration

The liver is a remarkable organ that can regenerate in response to injury. Depending on the extent of injury, the liver can undergo compensatory hyperplasia or fibrosis. Despite decades of research, the molecular mechanisms underlying these processes are poorly understood. Here, we developed a new model to study liver regeneration based on cryoinjury. To visualise liver regeneration at cellular resolution, we adapted the CUBIC tissue-clearing approach. Hepatic cryoinjury induced a localised necrotic and apoptotic lesion characterised by inflammation and infiltration of innate immune cells. Following this initial phase, we observed fibrosis, which resolved as regeneration re-established homeostasis in 30 days. Importantly, this approach enables the comparison of healthy and injured parenchyma with an individual animal, providing unique advantages to previous models. In summary, the hepatic cryoinjury model provides a fast and reproducible method for studying the cellular and molecular pathways underpinning fibrosis and liver regeneration. O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/550437v2_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@173e431org.highwire.dtl.DTLVardef@18a75b7org.highwire.dtl.DTLVardef@13662feorg.highwire.dtl.DTLVardef@19d47a8_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2023

Metabolism regulates muscle stem cell self-renewal by connecting the microenvironment and histone acetylation

Skeletal muscle contains a resident population of somatic stem cells capable of both self-renewal and differentiation. The signals that regulate this important decision have yet to be fully elucidated. Here we use metabolomics and mass spectrometry imaging (MSI) to identity a state of localized hyperglycaemia following skeletal muscle injury. We show that committed muscle progenitor cells exhibit an enrichment of glycolytic and TCA cycle genes and that extracellular monosaccharide availability regulates intracellular citrate levels and global histone acetylation. Muscle stem cells exposed to a reduced (or altered) monosaccharide environment demonstrate reduced global histone acetylation and transcription of myogenic determination factors (including myod1). Importantly, reduced monosaccharide availability was linked directly to increased rates of asymmetric division and muscle stem cell self-renewal in regenerating skeletal muscle. Our results reveal an important role for the extracellular metabolic environment in the decision to undergo self-renewal or myogenic commitment during skeletal muscle regeneration.

cell biology↗