Biology subjects

Oh, P.

Publications and source records attributed to Oh, P..

3 recordsLinked to original sources

bioRxiv2025

Reprogramming the Immune Suppressive Tumor Microenvironment in Glioma Enhances the Efficacy of Immune-Mediated Gene Therapy

Gliomas account for ~80% of primary malignant brain tumors. Many CNS WHO grade 2-3 and some grade 4 gliomas harbor mutant isocitrate dehydrogenase 1 (mIDH1), which causes a gain of function mutation (IDH1 R132H) leading to the production of 2-hydroxyglutarate (2HG). Mutant IDH1-induced 2HG, through epigenetic reprogramming elicits an immune-permissive tumor microenvironment (TME). An immunosuppressive mechanism in the glioma TME involves adenosine production via the ectoenzyme CD73. This study investigates mIDH1s influence on CD73 expression and adenosine levels. We demonstrate that mIDH1 glioma cells exhibit reduced CD73 expression, driven by DNA hypermethylation, leading to reduced adenosine levels. Since wtIDH1 gliomas have high CD73 expression, we evaluated CD73 blockade as an immunotherapy target. We show that CD73 inhibition used as monotherapy, did not improve survival in wtIDH1 glioma-bearing mice. However, when combined with immune-stimulatory Ad-TK (adenoviral vectors encoding herpes simplex virus thymidine kinase) and Ad-Flt3L (adenoviral vectors encoding FMS-like tyrosine kinase 3 ligand) gene therapy, CD73 blockade significantly enhanced therapeutic efficacy and increased anti-glioma effector T cell activity. These findings reveal that CD73 inhibition used in combination with immune stimulatory Ad-TK/Ad-Flt3L gene therapy may be an effective treatment for wtIDH1 gliomas, which could be readily translated to the clinical arena.

cancer biology↗

bioRxiv2023

A non-genetic model of vascular shunts informs on the cellular mechanisms of formation and resolution of arteriovenous malformations

Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to the transformation of a capillary into a shunt remain unclear and how shunts can be reverted into capillaries is poorly understood. Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in endothelial cell (EC) volume of venous origin (hypertrophic venous cells) are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signaling cell-autonomously regulates EC volume, demonstrating that our discoveries link with hereditary hemorrhagic telangiectasia (HHT)-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts. We demonstrate that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocates for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs.

cell biology↗

bioRxiv2022

TMEM100, a Lung-Specific Endothelium Gene

The heterogeneity of endothelium across different organs was recently explored using single-cell RNA-sequencing analysis. Compared to other organs, the lung exhibits a distinct structure composed of a thin layer of capillary for efficient gas exchange. In this study, we demonstrate that Tmem100 is a lung-specific endothelium gene.

physiology↗