Biology subjects

McGuone, D.

Publications and source records attributed to McGuone, D..

3 recordsLinked to original sources

bioRxiv2025

Interplay between cytokine and FGF2 signaling in induction of entosis and vasculogenic mimicry response in glioblastoma

Tumor vascularization is critical to survival of cancer cells, but is frequently perturbed leading to disorganized angiogenesis and emergence of alternative means of delivery of oxygen and nutrients, such as vasculogenic mimicry (VM). Understanding of VM and its relationship to endothelial vascularization has been hampered by the lack of comprehensive combination of in vivo clinical data and relevant in vitro models. We address this challenge by analyzing glioblastoma (GBM) tumors and clinically isolated cancer cells. This analysis strongly suggests a key role of macrophage-induced controlled cell death in emergence of VM. The results further point to entosis of cancer cells as a critical intermediate state in this process, enabled by mechano-chemical cell heterogeneity. We find evidence that macrophages can regulate endothelial angiogenesis and VM as two alternative vascularization mechanisms. These results reveal mechanistic underpinnings of VM and pave the way to predictive analysis of tumor progression.

cancer biology↗

bioRxiv2025

Acute temporal, regional, and cell-type specific NKCC1 disruption following severe TBI in the developing gyrencephalic brain.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in infants and toddlers, with limited treatment options and persistent neurological sequelae. We developed a multi-pathoanatomic lesion multi-insult (MuLMI) severe TBI model in piglets that replicates age-dependent damage patterns to the cortical ribbon observed in human patients with less injury in postnatal day (PND) 7 "infant" piglets and more extensive tissue damage in PND30 "toddler" piglets. Given that neuronal chloride homeostasis influences excitability, seizure susceptibility, and edema, we examined the developmental and injury-induced regulation of key cation-chloride cotransporters and modulators: NKCC1 (sodium-potassium-2-chloride cotransporter), KCC2 (potassium-chloride cotransporter), and the regulatory kinase SPAK, which are biomarkers of neuronal chloride concentrations. This study is the first to define the spatiotemporal expression and phosphorylation profiles of these proteins in the developing piglet brain. We found a perinatal shift in the ratio of KCC2:NKCC1 across the brain, driven primarily by protein abundance, rather than transcriptional levels. We hypothesized that toddler piglets would exhibit an increase in cortical NKCC1 and SPAK causing hyperexcitability and perhaps explaining their more severe, unilateral cortical damage. Severe TBI induced a transcriptional increase in Slc12a2 and Stk39, and a decrease in Slc12a5 in toddler piglets, but not infant piglets. We further found that infant piglets, not toddler piglets, upregulated SPAK and Tyrosine Receptor Kinase B (TRKB) protein in cortex after TBI, with minimal changes in NKCC1 and KCC2. However, phosphorylated NKCC1 (pNKCC1) was significantly upregulated in surviving cortical neurons after TBI in infant piglets and was unchanged in toddlers, despite more severe injury. These findings suggest that cortical neuronal NKCC1 activation may play a role in post-traumatic excitability or resilience in the immature brain and identify NKCC1 and/or SPAK as a potential therapeutic target. In human tissue, the KCC2:NKCC1 ratio also increased postnatally, and TBI caused region and cell-type specific dysregulation of pNKCC1. Our results establish piglets as a valuable model for investigating age-specific mechanisms of pediatric TBI and for testing targeted interventions, particularly for infant populations where seizure control remains a major clinical challenge.

neuroscience↗

bioRxiv2022

spARC Recovers Human Glioma Spatial SignalingNetworks with Graph Filtering

Biological networks operate within architectural frameworks that influence the state and function of cells through niche-specific factors such as exposure to nutrients and metabolites, soluble signaling molecules, and direct cognate cell-cell communication. Spatial omics technologies incorporate environmental information into the study of biological systems, where the spatial coordinates of cells may directly or indirectly encode these micro-anatomical features. However, they suffer from technical artifacts, such as dropout, that impede biological discovery. Current methods that attempt to correct for this fail to adequately integrate highly informative spatial information when recovering gene expression and modelling cell-cell dynamics in situ. To address this oversight, we developed spatial Affinity-graph Recovery of Counts (spARC), a data diffusion-based filtration method that shares information between neighboring cells in tissue and related cells in expression space, to recover gene dynamics and simulate signalling interactions in spatial transcriptomics data. Following validation, we applied spARC to 10 IDH-mutant surgically resected human gliomas across WHO grades II-IV in order to study signaling networks across disease progression. This analysis revealed co-expressed genes that border the interface between tumor and tumor-infiltrated brain, allowing us to characterize global and local structure of glioma. By simulating paracrine signaling in silico, we identified an Osteopontin-CD44 interaction enriched in grade IV relative to grade II and grade III astrocytomas, and validated the clinical relevance of this signaling axis using TCGA.

bioinformatics↗