文章基本信息

标题：Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas
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作者：Dileep D. Monie ; Cristina Correia ; Cheng Zhang 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2021
卷号：11
DOI：10.1038/s41598-021-90718-1
语种：English
出版社：Springer Nature
摘要：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 CCN1 high cells versus controls. Virus response programs, notably against HSV-1, and cytokine-mediated signaling pathways are highly enriched. Our results suggest that CCN1 high 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.