Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas

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,...

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Autores principales:	Dileep D. Monie, Cristina Correia, Cheng Zhang, Choong Yong Ung, Richard G. Vile, Hu Li
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cb6ba4dd71e340d2ac81300b41577f9c
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spelling	oai:doaj.org-article:cb6ba4dd71e340d2ac81300b41577f9c2021-12-02T16:53:19ZModular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas10.1038/s41598-021-90718-12045-2322https://doaj.org/article/cb6ba4dd71e340d2ac81300b41577f9c2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90718-1https://doaj.org/toc/2045-2322Abstract 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.Dileep D. MonieCristina CorreiaCheng ZhangChoong Yong UngRichard G. VileHu LiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dileep D. Monie Cristina Correia Cheng Zhang Choong Yong Ung Richard G. Vile Hu Li Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas
description	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.
format	article
author	Dileep D. Monie Cristina Correia Cheng Zhang Choong Yong Ung Richard G. Vile Hu Li
author_facet	Dileep D. Monie Cristina Correia Cheng Zhang Choong Yong Ung Richard G. Vile Hu Li
author_sort	Dileep D. Monie
title	Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas
title_short	Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas
title_full	Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas
title_fullStr	Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas
title_full_unstemmed	Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas
title_sort	modular network mechanism of ccn1-associated resistance to hsv-1-derived oncolytic immunovirotherapies for glioblastomas
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cb6ba4dd71e340d2ac81300b41577f9c
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Modular network mechanism of CCN1-associated resistance to HSV-1-derived oncolytic immunovirotherapies for glioblastomas

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