Medical Scientist Training Program, Mayo Clinic College of Medicine and Science, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
Department of Immunology, Mayo Clinic College of Medicine and Science, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
Sci Rep. 2021 May 27;11(1):11198. doi: 10.1038/s41598-021-90718-1.
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 cells versus controls. Virus response programs, notably against HSV-1, and cytokine-mediated signaling pathways are highly enriched. Our results suggest that CCN1 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.
胶质母细胞瘤（GBM）是成人中最常见和最致命的原发性脑恶性肿瘤。溶瘤病毒（OV）免疫疗法以一种引发抗肿瘤免疫的方式选择性地杀死 GBM 细胞。细胞通讯网络因子 1（CCN1）是一种在大多数 GBM 微环境中发现的蛋白质，其表达预测对 OV 的耐药性，特别是单纯疱疹病毒 1（HSV-1）。本研究旨在了解细胞外 CCN1 如何改变 GBM 细胞内状态以赋予 OV 耐药性。对 LN229 人 GBM 转录组的蛋白质-蛋白质相互作用网络信息流分析确定了 39 个新节点和 12 个二元边缘，这些节点和边缘在 CCN1 细胞与对照细胞中主导信息流。病毒反应程序，特别是针对 HSV-1 的反应程序，以及细胞因子介导的信号通路高度富集。我们的结果表明，CCN1 状态利用 IDH1 和 TP53，并增加对 RPL6、HUWE1 和 COPS5 的依赖性。为了验证，我们在另外 65 个 GBM 细胞系（CCLE）和 174 个临床 GBM 患者样本（TCGA）数据集上重现了我们的发现。我们通过我们的通用网络建模和系统水平分析得出结论，CCN1 通过 GBM 中的几种先天免疫途径发出信号，在转导之前抑制 HSV-1 OV。破坏该网络的干预措施可能克服免疫病毒疗法的耐药性。
