ABS 118: Molecular Mechanisms of HCMV-Induced Malignancy in Glioblastoma: Investigation into Surface Receptor Dysregulation and Therapeutic Strategies

Austin Jacobson ¹ , Noe Mercado ² , Andrea Schmidt ² , Philippa Vaughn-Beaucaire ² , Sean Lawler ²

¹ Brown University
² Pathology and Laboratory Medicine, Brown University

Van Wickle (2025) Volume 1, ABS 118

Introduction: Glioblastomas (GBM) are the most lethal and most common malignant primary CNS cancer, marked by therapy resistance and tumor heterogeneity. Despite treatment, median survival is only 14 months. Recent studies suggest that human cytomegalovirus (HCMV) promotes GBM malignancy; as seroprevalence rises to 60-80% in developed countries, its potential impact presents a significant public health concern. Studies of infected GBM cell lines show increased proliferation, angiogenesis, and therapy resistance. However, HCMV’s oncomodulatory role remains unclear.
The Lawler Lab aims to investigate the molecular mechanisms underlying CMV pathogenesis in GBM. Using a UL18-Luciferase-tagged viral construct, we observed that one patient derived glioma stem cell was highly susceptible to viral infection. Furthermore, infection increased cell viability by over 25%, an advantage eradicated with treatment of antiviral drugs in combination with current standard-of-care treatment (chemo/radiotherapy). Notably, reduction was weaker in HCMV+ cells treated with standard-of-care alone, suggesting antivirals as a potential combinatorial therapeutic.
To better understand the functional processes involved in HCMV-induced enhanced malignancy, we integrated RNA sequencing and proteomic expression analysis screens of HCMV-infected glioma cells to uncover a novel set of differentially expressed surface receptors. To determine whether these receptors play a conserved role in HCMV+ tumor pathogenesis, we are collaborating with the Erasmus Medical Center Neurosurgery Department to study additional patient derived glioma stem cell lines. We plan to use these lines to perform qPCR analysis of key receptors identified in our screen—PDGFRα, LAMA5, ITGB1, and ANXA1,4,7—before and after infection. Preliminary results with PDGFRa show a correlation between cellular expression and infectability, suggesting it as a biomarker and therapeutic target against HCMV susceptibility in GBM patients. Our next step will be to use siRNA and transfection-based differential expression systems to evaluate the roles of these receptors in CMV+ malignancy-associated phenotypes, including viability, growth and invasiveness.