Biology subjects

Edwards, D. M.

Publications and source records attributed to Edwards, D. M..

4 recordsLinked to original sources

bioRxiv2026

Single-cell profiling of synchronous multi-organ metastasis reveals a systemic CD74+ lipid-associated macrophage niche driving polymetastatic breast cancer

Systemic, multi-organ metastasis is the primary cause of breast cancer mortality, yet the biological mechanisms that allow disseminated tumor cells to simultaneously colonize physiologically diverse tissues remain poorly understood. Current paradigms focus on organ-specific tropism, largely overlooking the potential for systemic, conserved and synchronized programs that facilitate widespread colonization. Here, we present a high-resolution, multi-organ atlas of metastatic ecosystems and their niches using a synchronous model of brain, lung, liver, and bone metastasis combined with in vivo proximal niche labeling and single-cell RNA sequencing. We identify a remarkably conserved proximal niche program defined by the accumulation of CD74+ lipid-associated, metastasis-associated macrophages (LA-MAMs) across all metastatic sites. CD74+ LA-MAMs are characterized by a unique metabolic-immune signature and drive T cell suppression. We show that the cytokine Macrophage Migration Inhibitory Factor (MIF), secreted by metastatic cells, acts as the universal paracrine mediator that instructs the LA-MAM phenotype via the CD74 receptor. Interference of the MIF-CD74 axis effectively disrupts the LA-MAM niche, mitigates T cell exhaustion, and reduces metastatic burden across all organs. Analysis of a 100-patient cohort of metastasis samples from different sites confirms that the MIF-CD74 axis is a hallmark of human multi-organ colonization and independently predicts poor post-metastasis survival. Our findings define a synchronized and systemic metastatic niche that can be targeted, providing a mechanistic rationale for neutralizing the MIF-CD74 axis to treat polymetastatic breast cancer.

cancer biology↗

bioRxiv2025

Targeting mTORC2 in lung squamous cell carcinoma improves anti-tumor immunity through the PSGL-1-VISTA axis

Targeted therapies have improved survival for lung adenocarcinoma patients. However, similar advances are lacking for lung squamous carcinoma (LUSC). Advances in immunotherapy have shown some promise, but the overall response rate remains low in LUSC. Here, we demonstrate that the mTORC2 signaling pathway represents an actionable target in LUSC to improve anti-tumor immune responses. We show that genetic alterations affecting the mTORC2 pathway are common among patients with LUSC tumors, and targeting mTORC2 reduces LUSC tumor growth in mouse models. Transcriptomics reveal that mTORC2-deficient LUSC cells exhibit reduced expression of glycolytic and hypoxia-related genes. In agreement, loss of mTORC2 signaling decreases lactate levels in tumor-interstitial fluid, creating reduced acidity within the tumor microenvironment. Interestingly, mTORC2-deficient LUSC cells also exhibited reduced expression of the pH-sensitive VISTA ligand PSGL-1 in a HIF-2 dependent mechanism. LUSC patients, but not those with LUAD, display a positive correlation in expression between HIF-2 and PSGL-1, suggesting a distinct association among mTORC2, HIF-2, and immune responses in LUSC. Indeed, mTORC2 loss-of-function enhanced CD8+ T cell activation in tumors, while use of anti-VISTA immunotherapy reduced LUSC tumor burden only in the presence of intact mTORC2 signaling. Collectively, these data describe an important role of mTORC2 signaling in LUSC tumors and demonstrate the therapeutic potential of targeting the mTORC2/PSGL-1/VISTA axis in patients that are non-responsive to current therapies.

cancer biology↗

bioRxiv2022

Synergising single-cell resolution and 4sU labelling boosts inference of transcriptional bursting

Despite the recent rise of RNA-seq datasets combining single-cell (sc) resolution with 4-thiouridine (4sU) labelling, analytical methods exploiting their power to dissect transcriptional bursting are lacking. Here, we present a mathematical model and Bayesian inference implementation to facilitate genome-wide joint parameter estimation and confidence quantification. We demonstrate that, unlike conventional scRNA-seq, 4sU scRNA-seq resolves temporal parameters and furthermore boosts inference of dimensionless parameters via a synergy between single-cell resolution and 4sU labelling. We applied our method to published 4sU scRNA-seq data and linked with ChIP-seq data, uncovering previously obscured associations between different parameters and histone modifications.

bioinformatics↗

bioRxiv2021

Genome-wide chromosomal association of Upf1 is linked to Pol II transcription in Schizosaccharomyces pombe

Although the RNA helicase Upf1 has hitherto been examined mostly in relation to its cytoplasmic role in nonsense mediated mRNA decay (NMD), here we report high-throughput ChIP data indicating genome-wide association of Upf1 with active genes in Schizosaccharomyces pombe. This association is RNase sensitive and it correlates with Pol II transcription and mRNA expression levels. While changes in Pol II occupancy were detected at only some genes in a Upf1-deficient (upf1{Delta}) strain, there is an increased Ser2 Pol II signal at all highly transcribed genes examined by ChIP-qPCR. Furthermore, upf1{Delta} cells are hypersensitive to the transcription elongation inhibitor 6-azauracil and display Pol II abnormalities suggestive of Pol II hyperphosphorylation. A significant proportion of the genes associated with Upf1 in wild-type conditions are also mis-regulated in upf1{Delta}. These data envisage that by operating on the nascent transcript Upf1 might influence Pol II phosphorylation and transcription.

molecular biology↗