Biology subjects

Trim, P. J.

Publications and source records attributed to Trim, P. J..

4 recordsLinked to original sources

bioRxiv2026

STILL-13C: Spatial tracing of isotopically labelled lipids with 13C reveals metabolic heterogeneity in intact tissues

Lipid metabolism is dynamically rewired across tissues in response to developmental, environmental and therapeutic cues. This adaptation drives treatment resistance in a range of human pathologies, but current lipidomic techniques fail to capture the underlying mechanisms, relying on steady-state measurements from homogenised samples that obscure spatial heterogeneity and pathway flux. Here we introduce spatial tracing of isotopically labelled lipids (STILL-13C), a workflow that uses stable isotope tracing and high-resolution mass spectrometry imaging (MSI) to map lipid metabolic flux directly in intact human tissues with unprecedented pathway coverage. STILL-13C overcomes longstanding limitations of bulk and MSI-based analyses by spatially resolving isotopologue labelling of simple and complex lipids, enabling simultaneous tracing of fatty acid synthesis, remodelling and multiple convergent pathways required for phospholipid assembly, while preserving tissue architecture and regional metabolic context. Applied to patient-derived prostate cancer explants cultured ex vivo, STILL-13C revealed heterogeneity in lipid pathway activity between neighbouring epithelial regions and spatially resolved responses to pathway inhibition. This work establishes a broadly applicable platform for investigating spatial heterogeneity in lipid metabolic flux and its perturbation in intact tissues.

molecular biology↗

bioRxiv2025

Cognitive impairment and progressive neuroinflammation in mucopolysaccharidosis IIIA mice expressing the R245H Sgsh variant

Mucopolysaccharidosis (MPS) type IIIA (Sanfilippo syndrome) is an inherited childhood-onset dementia caused by insufficient SGSH enzymatic activity and subsequent accumulation of partially degraded heparan sulfate glycosaminoglycans. One of the most prevalent mutations is the Arg245His variant, representing up to 58% of mutations in some populations. Whilst other mouse models exist, none exhibit the mutations seen in humans, thus their amenability to testing of therapeutics such as pharmacological chaperones, which are often mutation-dependent, is limited. We have used CRISPR/Cas 9 gene editing to generate the first SgshR245H knock-in mouse model of MPS IIIA, which subsequently underwent extensive phenotyping. SgshR245H mouse brain exhibited progressive accumulation of heparan sulfate, endo/lysosomal system expansion and elevated levels of GFAP-reactive astroglial staining and activated microglia. Significant perturbation in several novel lipid species was observed in the CA1 region of the hippocampus using Matrix-Assisted Laser Desorption/Ionisation Mass Spectrometry Imaging. Spatial memory deficits were apparent in the Morris Water Maze probe and Y-maze tests, and Elevated Plus Maze exploration revealed reduced anxiety-like behaviours. SgshR245H MPS IIIA mice recapitulate key characteristics of the human disorder and represent a useful tool for studying disease pathogenesis and evaluating novel therapeutic approaches. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/691757v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@17ee5bforg.highwire.dtl.DTLVardef@1d7e23org.highwire.dtl.DTLVardef@445800org.highwire.dtl.DTLVardef@ed7dad_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Substrate reduction therapy in a Drosophila melanogaster model of Sanfilippo syndrome

Sanfilippo syndrome, or mucopolysaccharidosis (MPS) types A, B, C or D, are neurodegenerative lysosomal storage disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism. Several treatments are under evaluation for these conditions including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, recent outcomes from a Phase III clinical trial have shown that high dose oral genistein does not significantly improve neurodevelopmental outcomes in MPS III patients. Here, we have tested an N-acetylglucosamine (GlcNAc) analogue inhibitor, 4-deoxy-GlcNAc peracetate, at reducing HS accumulation in cells from patients with Sanfilippo syndrome as a novel substrate reduction therapy. We then confirmed the capacity of this compound to modulate substrate accumulation in vivo in a Sanfilippo Drosophila model. Treatment with this compound significantly reduced HS in cultured MPS IIIA patient fibroblasts in a time-dependent manner. Neuronal and ubiquitous knockdown Drosophila models of MPS IIIC displaying elevated heparan sulfate and behavioural defects exhibited reduced HS burden relative to vehicle-treated controls following oral feeding with the GlcNAc analogue inhibitor. These findings indicate that this compound may be beneficial in slowing the accumulation of HS and may represent a novel therapeutic for Sanfilippo syndrome.

neuroscience↗

bioRxiv2020

Lipidomic profiling of clinical prostate cancer reveals targetable alterations in lipid composition

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Herein, we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n=21), independent tissues (n=47), and primary prostate explants cultured with a clinical AR antagonist, enzalutamide (n=43). Significant differences in lipid composition were detected and spatially visualized in tumors compared to matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and PL composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting of altered tumor-related lipid features, via inhibition of acetyl CoA carboxylase 1, significantly reduced cellular proliferation in tissue explants (n=13). This first characterization of the prostate cancer lipidome in clinical tissues revealed enhanced fatty acid synthesis, elongation and desaturation as tumor-defining features, with potential for therapeutic targeting.

cancer biology↗