Abstract
Glioblastomas (GBMs) are the most common and lethal primary brain malignancy in adults. Oncolytic virus (OV) immunotherapies selectively kill GBM cells in a manner that elicits antitumor immunity. Cellular communication network factor 1 (CCN1), a protein found in most GBM microenvironments, expression predicts resistance to OVs, particularly herpes simplex virus type 1 (HSV-1). This study aims to understand how extracellular CCN1 alters the GBM intracellular state to confer OV resistance. Protein–protein interaction network information flow analyses of LN229 human GBM transcriptomes identified 39 novel nodes and 12 binary edges dominating flow in CCN1high cells versus controls. Virus response programs, notably against HSV-1, and cytokine-mediated signaling pathways are highly enriched. Our results suggest that CCN1high states exploit IDH1 and TP53, and increase dependency on RPL6, HUWE1, and COPS5. To validate, we reproduce our findings in 65 other GBM cell line (CCLE) and 174 clinical GBM patient sample (TCGA) datasets. We conclude through our generalized network modeling and system level analysis that CCN1 signals via several innate immune pathways in GBM to inhibit HSV-1 OVs before transduction. Interventions disrupting this network may overcome immunovirotherapy resistance.
Highlights
Glioblastomas (GBMs) are the most common and lethal primary brain malignancy in adults
Cellular communication network factor 1 (CCN1) is a protein found in the extracellular matrix (ECM) of the majority of GBMs and is predictive of resistance to Oncolytic virus (OV), those derived from HSV-18. CCN1high expressing GBMs confer worse progression-free and overall survival p rognoses[9]
Our novel genome-wide flow-based systems strategy unravels protein–protein interactions that are important in GBM development and progression
Summary
Glioblastomas (GBMs) are the most common and lethal primary brain malignancy in adults. Cellular communication network factor 1 (CCN1), a protein found in most GBM microenvironments, expression predicts resistance to OVs, herpes simplex virus type 1 (HSV-1). We conclude through our generalized network modeling and system level analysis that CCN1 signals via several innate immune pathways in GBM to inhibit HSV-1 OVs before transduction. Interventions disrupting this network may overcome immunovirotherapy resistance. The disease comes with a dismal prognosis, often with expected survival just over a year when treated with surgery, chemotherapy, and r adiation[2] Immunotherapies such as checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are emerging as a fourth arm in the treatment arsenal against GBM. Proteins, and interactions critical to CCN1high GBM phenotype that are potentially druggable and can guide the engineering of precision OVs
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