Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas.
Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas.
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DOI：
10.1038/s41598-021-90718-1
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发表时间：
2021-05-27
影响因子：
4.6
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Monie DD;Correia C;Zhang C;Ung CY;Vile RG;Li H
胶质母细胞瘤是成人最常见、最致命的原发脑部恶性肿瘤。溶瘤病毒(OV)免疫疗法以诱导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，它的表达预测了对OV，特别是1型单纯疱疹病毒(HSV-1)的耐药性。本研究旨在了解细胞外CCN1如何改变基底膜细胞内状态以赋予OV抵抗。对LN229人GBM转录本进行的蛋白质-蛋白质相互作用网络信息流分析发现，与对照组相比，39个新节点和12个二元边在CCN1High细胞中占据主导地位。病毒反应程序，特别是针对HSV-1的反应程序和细胞因子介导的信号通路高度丰富。我们的结果表明，CCN1高状态利用了IDH1和TP53，并增加了对RPL6、HUWE1和COPS5的依赖。为了验证，我们在65个其他GBM细胞系(CCLE)和174个临床GBM患者样本(TCGA)数据集中复制了我们的发现。通过我们的广义网络建模和系统水平分析，我们得出结论：CCN1信号在GBM中通过几个天然免疫途径在转导之前抑制HSV-1OVS。破坏这一网络的干预措施可能会克服免疫病毒疗法的耐药性。
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.
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