Biology subjects

Jamieson, N. B.

Publications and source records attributed to Jamieson, N. B..

3 recordsLinked to original sources

bioRxiv2025

Blocking Minor Intron Splicing Disrupts DNA Repair and Overcomes Therapy Resistance in Prostate and Breast Cancer

The minor spliceosome (MiS) is a specialized RNA-processing machinery upregulated in cancer, promoting oncogene expression. We uncovered an adaptive resistance mechanism driven by secretion of extracellular vesicles enriched in U6atac snRNA, which amplifies MiS activity and promotes therapy resistance. Here, we show that U6atac snRNA, a crucial MiS component, reverses this process when depleted, revealing it as a druggable vulnerability in therapy-resistant prostate and breast cancers. U6atac knockdown triggers R-loop-mediated DNA damage while impairing repair by downregulating key DNA repair factors, disabling both homologous recombination and non-homologous end joining. This dual effect sensitizes prostate and breast tumors to PARP inhibitors, cisplatin, and radiation, independent of BRCA status. Across multiple in vitro and in vivo models, MiS targeting demonstrates tumor-selective activity with minimal toxicity. These findings position U6atac as a central regulator of genome stability and establish MiS targeting as a promising approach to potentiate genotoxic therapy and overcome resistance. Statement of significanceU6atac, a minor spliceosome component, is a crucial regulator of genome stability in cancer. Its knockdown triggers R-loop-driven DNA damage, downregulates DNA repair genes, and sensitizes tumors to DNA-damaging therapies while simultaneously blocking resistance mechanisms. Thus, minor spliceosome knockdown is a tumour-selective and broadly applicable therapeutic strategy.

cancer biology↗

bioRxiv2025

Neuroinflammation driven by TLR7 activation in mice results in a global inflammatory response driving circuit-specific changes in neuronal gene expression

Interactions between the brain and immune system play a key role in the aetiology of brain disorders, with inflammation emerging as a potential causal factor in subsets of major depressive disorder, particularly those resistant to treatment. The causal mechanisms through which immune activation can drive depressive symptoms remain elusive, limiting the ability to develop new targeted therapies. Using a mouse model of neuroinflammation, involving a TLR7/8 agonist, we found central and systemic inflammation alongside anhedonia-like behaviours, altered thalamostriatal signalling and infiltration of peripheral immune cells into the brain. Here, we sought to use combined whole-brain transcriptome and spatial transcriptomics approaches to determine whether Aldara-driven neuroinflammation resulted in consistent immune and neurobiological changes throughout the brain. We found evidence of strong immune activation throughout the brain, with astrocytes displaying a strong inflammatory profile that was relatively uniform throughout. However, we found that this global inflammatory signal led to regionally-specific changes in gene expression, particularly reduced expression of genes associated with synaptic function in brain areas underlying mood and anxiety, such as ventral striatum and amygdala. Our data suggest potential mechanisms through which astrocytes regulate neuronal function in response to inflammation.

neuroscience↗

bioRxiv2024

Spatial resolution of transcriptomic plasticity states underpinning lethal morphologies in lung adenocarcinoma

Adenocarcinoma of the lung (LUAD) is a common and highly lethal disease. Clinical grading of disease strongly predicts recurrence and survival after surgery and is determined by morphological assessment of histological growth patterns in resected tumours. The molecular basis of growth pattern is poorly understood at present, as are the mechanisms linking growth pattern to recurrence and death. Interestingly, the two archetypal lethal morphologies, solid and micropapillary patterns, are characterised by their biphasic appearance. Both have an epithelial fraction which is in direct stromal contact, and a fraction which is not. This morphological variance seems likely to represent plasticity, and to be causally linked to mechanisms of virulence. To investigate the gene expression changes related to growth pattern both intra- and intertumoral, we applied spatial transcriptomics (Nanostring GeoMx DSP) to tissue microarray specimens of primary resected human lung adenocarcinoma. Using a variety of region-of-interest (ROI) selection strategies, we sampled 160 pure epithelial ROIs across 7 distinct morphological features of LUAD from 51 patients. Analyses of gene expression reveal fundamental trajectories connecting growth patterns, and crucial modes of plasticity which underly high-risk morphologies. These modes suggest mechanisms for the origins of growth pattern and mechanisms of virulence. Our work highlights dramatic divergence in gene expression programmes between highly lethal but morphologically diverse modes of tumour growth. Furthermore, it provides an explanation for how microscopically localised hypoxia in the primary tumour helps to establish and maintain survival strategies which ultimately determine morphology-specific mechanisms of tumour metastasis, suggesting new therapeutic vulnerabilities.

cancer biology↗