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

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.


COPS5
COP9 constitutive photomorphogenic homolog subunit 5 regulator of signaling pathways, reported to be involved in the degradation of cyclin-dependent kinase inhibitor CDKN1B/p27Kip1

IL32
Interleukin 32 pro-inflammatory cytokine that can induce cells of the immune system (such as monocytes and macrophages) to secrete inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and IL-6. In addition, it can also induce the production of chemokines such as IL-8 and MIP-2 / CXCL2.

IRF7
Interferon regulatory factor 7 Play a role in the transcriptional activation of virusinducible cellular genes, including the type I interferon genes. In particular, IRF7 regulates many interferon-alpha genes. Constitutive expression of IRF7 is largely restricted to lymphoid tissue, largely plasmacytoid dendritic cells, whereas IRF7 is inducible in many tissues. Multiple IRF7 transcript variants have been identified, although the functional consequences of these have not yet been established.

SPTBN1
Spectrin beta chain, brain 1 functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles

STAT1
Signal transducer and activator of transcription 1 mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens

STAT2
Signal transducer and activator of transcription 2 forms a complex with STAT1 and IFN regulatory factor family protein p48 (IRF9), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly.

STIP1
Stress induced phosphoprotein 1 coordinates the functions of HSP70 (see HSPA1A; MIM 140550) and HSP90 (see HSP90AA1; MIM 140571) in protein folding. It is thought to assist in the transfer of proteins from HSP70 to HSP90 by binding both HSP90 and substrate-bound HSP70. STIP1 also stimulates the ATPase activity of HSP70 and inhibits the ATPase activity of HSP90, suggesting that it regulates both the conformations and ATPase cycles of these chaperones

SUMO1
Small ubiquitin-related modifier 1 a member of the SUMO (small ubiquitin-like modifier) protein family. It functions in a manner similar to ubiquitin in that it is bound to target proteins as part of a post-translational modification system. However, unlike ubiquitin which targets proteins for degradation, this protein is involved in a variety of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability.

THBD
Thrombomodulin integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin. It reduces blood coagulation by converting thrombin to an anticoagulant enzyme from a procoagulant enzyme

TUT1
Terminal uridylyl transferase 1, U6 snRNA-specific adds and removes nucleotides from the 3' end of small nuclear RNAs and select mRNAs and may function in controlling gene expression and cell proliferation.

UBC
Ubiquitin C protein degradation, DNA repair, cell cycle regulation, kinase modification, endocytosis, and regulation of other cell signaling pathways. CCCH-type zinc finger protein that is thought to prevent infection by retroviruses. Studies of the rat homolog indicate that the protein may primarily function to inhibit viral gene expression and induce an innate immunity to viral infection.