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Comparative proteomics for identification of type I interferon response in primary human glioblastoma multiforme cells

ABSTRACT: Oncolytic virus therapy is a promising direction for cancer treatment. Numerous oncolytic virus strains are under development or examined in clinical trials, there are examples of FDA approved virus vaccines. Although evident progress exists, oncolytic viruses still suffer low efficiency and the mechanisms of their action remain poorly understood. Defects in antiviral mechanisms that include type I interferon (IFN) signaling, contribute to sensitivity of malignant cells to oncolytic viruses, however, this sensitivity significantly differs for different malignant cells. In this project, we present a collection of representative proteomics data for eight primary glioblastoma multiforme (GBM) cell cultures and one culture of normal astrocytes with established sensitivity to type I IFNs that comprehensively characterize the GBM cell responses to type I IFNs. Project consists of three parts: (1) label-free proteomics of primary GBM cultures on Orbitrap Fusion Lumos; (2) label-free proteomics of primary GBM and normal astrocytes on Orbitrap QExactive HF; (3) label-based proteomics of wild type, IFIT3-deficient and PLSCR1-deficient DBTRG-05MG cells (ATCC) on Q-Exactive Plus.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Primary Cell Line Cell

DISEASE(S): Glioblastoma

SUBMITTER: Elizaveta Solovyeva

LAB HEAD: Irina A Tarasova

PROVIDER: PXD022836 | Pride | 2022-02-03

REPOSITORIES: Pride

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Comparative proteomics for identification of type I interferon response in primary human glioblastoma multiforme cells

Project description:Oncolytic virus therapy is a promising direction for cancer treatment. Numerous oncolytic virus strains are under development or examined in clinical trials, there are examples of FDA approved virus vaccines. Although evident progress exists, oncolytic viruses still suffer low efficiency and the mechanisms of their action remain poorly understood. Defects in antiviral mechanisms that include type I interferon (IFN) signaling, contribute to sensitivity of malignant cells to oncolytic viruses, however, this sensitivity significantly differs for different malignant cells. In this project, we present a collection of representative proteomics data for eight primary glioblastoma multiforme (GBM) cell cultures and one culture of normal astrocytes with established sensitivity to type I IFNs that comprehensively characterize the GBM cell responses to type I IFNs. Project consists of three parts: (1) label-free proteomics of primary GBM cultures on Orbitrap Fusion Lumos (a separate dataset); (2) label-free proteomics of primary GBM and normal astrocytes on Orbitrap QExactive HF; (3) label-based proteomics of wild type, IFIT3-deficient and PLSCR1-deficient DBTRG-05MG cells (ATCC) on Q-Exactive Plus.

2022-02-03 | PXD022906 | Pride

High throughput characterization of human glioblastoma multiforme cell response to Type 1 interferons

Project description:Oncolytic virus therapy is a promising direction for cancer treatment. Numerous oncolytic viruses are under development or examined in clinical trials, there are examples of FDA approved virus vaccines. Although evident progress exists, oncolytic viruses still suffer low efficiency and the mechanisms of their action remain poorly understood. Defects in antiviral mechanisms that include type I interferon (IFN) signaling, contribute to sensitivity of malignant cells to oncolytic viruses, however, this sensitivity significantly differs for different malignant cells. In this project, we present a collection of representative transcriptomics and proteomics data for primary glioblastoma multiforme (GBM) cell cultures with established sensitivity to type I IFNs and the comprehensive characterization of GBM responses at both protein and RNA levels. Analysis demonstrated that GBM cells can respond to treatment by extreme upregulation of IFN-induced genes that is very similar to classic response in normal human cells. GBM cultures can significantly differ from each other by a value of transcriptome and proteome changes that are well correlated with sensitivity tests. In our data, upregulation of IFIT1/2/3, OAS1/2/3/L, MX1/2 among the others, was a reproducible marker for the developed resistance of GBM cells to vesicular stomatitis virus (VSV).

2021-12-29 | GSE163949 | GEO

Comparative proteomics for identifying specific alterations within interferon response pathways in human glioblastoma multiforme and osteosarcoma cells

Project description:An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where oncolytic virus therapy would be most effective. We quantified changes in protein abundances in glioblastoma multiforme (GBM) and osteosarcoma cell lines that differ in the ability to induce resistance to vesicular stomatitis virus (VSV) infection in response to type I interferon (IFN) treatment. In IFN-treated samples we observed an up-regulation of protein products of some IFN-regulated genes (IRGs). In total, the proteome analysis revealed up to 20% more proteins encoded by IRGs in the glioblastoma cell line, which develops resistance to VSV infection after pre-treatment with IFN. In both cell lines protein-protein interaction and signaling pathway analyses have revealed a significant stimulation of processes related to type I IFN signaling and defense responses to viruses. The study has shown that the up-regulation of IRG proteins induced by the IFNα treatment of GBM cells can be detected at the proteome level. Similar analyses could be applied for revealing functional alterations within the antiviral mechanisms in glioblastoma samples, accompanying by acquisition of sensitivity to oncolytic viruses.

2022-06-09 | PXD022868 | Pride

Immune Escape via A Transient Gene Expression Program Enables Productive Replication of A Latent Pathogen

Project description:How type I / II interferons (IFNs) prevent periodic re-emergence of latent pathogens in tissues of diverse cell-types remains unknown. Using homogenous neuron cultures latently-infected with herpes simplex virus (HSV), we show that extrinsic type I or II IFN act directly on neurons to induce unique gene expression signatures and inhibit the reactivation-specific burst of viral genome-wide transcription called Phase I. Surprisingly, IFNs suppressed reactivation only during a limited period early in Phase I preceding productive virus growth. Sensitivity to type II IFN was selectively lost if viral ICP0, which normally accumulates later in Phase I, was expressed prior to reactivation. Thus, IFNs suppress reactivation by preventing initial expression of latent genomes but are ineffective once Phase I viral proteins accumulate and limit IFN action. This demonstrates that inducible reactivation from latency is only transiently sensitive to IFNs. Moreover, it illustrates how latent pathogens escape host immune control to periodically replicate by rapidly deploying an interferon-resistant state.

2017-02-03 | GSE90744 | GEO

Copy number variations analysis by CytoscanHD array of 33 human pleural mesothelioma cell lines

Project description:We performed a cytoscanHD array to analyze copy number variations in the genome of 33 human pleural mesothelioma cell lines established from patient pleural effusion. We were particularly interested in the analysis of the p21.3 region of chromosome 9 which contains CDKN2A tumor suppressor genes and the gene encoding type I interferons that are often deleted and confer sensitivity to oncolytic Measles virus

2019-07-17 | GSE134349 | GEO

Model based Rational Design of an Oncolytic Virus with Improved Therapeutic Potential

Project description:Oncolytic viruses are complex biological agents that interact at multiple levels with both tumor and normal tissues. Anti-viral pathways induced by interferon are known to play a critical role in determining tumor cell sensitivity and normal cell resistance to infection with oncolytic viruses. Here we pursue a synthetic biology approach to identify methods that enhance anti-tumor activity of oncolytic viruses through suppression of IFN signaling. Based on the mathematical analysis of multiple strategies, we hypothesize that a positive feedback loop, established by virus-mediated expression of a soluble interferon-binding decoy receptor, increases tumor cytotoxicity without compromising normal cells. Oncolytic rhabodviruses engineered to express a secreted interferon antagonist have improved oncolytic potential in cellular cancer models, and display improved therapeutic potential in tumor-bearing mice. Our results demonstrate the potential of this methodology in evaluating potential caveats of viral immune evasion strategies and improving the design of oncolytic viruses. The following series of microarray experiments was utilized to assess the impact of cloning an IFN decoy receptor isolated from vaccinia virus termed B19R on the transcriptional response against an IFN sensitive maraba virus strain termed MG1. RNA extraction was performed 24h post infection in 786-0 cells. Duplicate samples were pooled, and hybridized on Affymetrix human gene 1.0 ST arrays according to manufacturer instructions. Data analysis was performed using AltAnalyze. Briefly, probeset filtering implemented a DABG threshold of 70 & pV<0.05 and utilized exclusively constitutively expressed exons to assess levels of gene expression.

2013-06-01 | E-MTAB-1636 | biostudies-arrayexpress

Alternative classification of glioblastoma based on BUB1B-inhibition sensitivity

Project description:We created a computational framework with which to predict BUB1B-GLEBS sensitivity based on gene expression data from BUB1B-inhibition sensitive (BUB1BS) or resistant (BUB1BR) GBM stem cells (GSCs), astrocytes, and neural progenitors. Our classifier examines the expression of 838 genes comprising the BUB1BS signature. Applying this scheme to GBM patient tumor data stratified tumors into BUB1BS and BUB1BR subtypes, revealing that BUB1BS patients have a significantly worse prognosis regardless of their tumor's development subtype (i.e., classical, mesenchymal, neural, proneural). Applying the same scheme to drug sensitivity profiles predicts that BUB1BS cells to be more sensitive to Raf inhibitors as well as other drugs such as type I and II topoisomerase inhibitors among other drugs. Functional genomic profiling of BUB1BR versus BUB1BS GBM isolates revealed differentially reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation. Taken together, our results show that BUB1BR/S classification of GBM tumors, in addition to predicting BUB1B-inhibition sensitivity, may help predict cancer aggressiveness and sensitivity to multiple anti-cancer drugs.

2018-02-01 | GSE94874 | GEO

Apolipoprotein A1-Manipulated Cholesterol Efflux Subverts the Phagocytic Fragility of TAMs and Improves Oncolytic Viro-Immunotherapy in Glioblastoma [Tumor RNA-seq]

Project description:We found that overexpression of APOA1 in glioblastoma (GBM) promotes cholesterol efflux from TAMs and restores phagocytosis and antigen presentation. Therefore, we constructed a recombinant oncolytic adenovirus expressing APOA1 to carry the cholesterol regulatory elements of TAMs. AdV-APOA1 exhibited better antitumor effects than AdV-Ctrl in several orthotopic GBM tumor models. Further, we collected virus-treated GL261-CAR tumors for RNA-seq to reveal differences in biological processes between them. Specifically, intracranial 14-day GL261-CAR-bearing C57BL/6J mice were i.t. injected with 1 × 108 PFU AdV-Ctrl or 1 × 108 PFU AdV-APOA1. The tumor bulks were then collected to perform transcriptome RNA-seq analysis 3 days after virus injection.

2022-05-04 | GSE201976 | GEO

Prospective, open, single-arm clinical study of novel oncolytic virus against CTC micrometastasis of lung cancer, colorectal cancer and other malignant tumors

Project description:Interventions: Lung Cancer group:Novel Oncolytic Virus;Colorectal Cancer group:Novel Oncolytic Virus Primary outcome(s): objective response rate;overall survival;Quality of life;Safety;disease control rate;disease-free survival Study Design: Single arm

| 2725682 | ecrin-mdr-crc

Subclone of resistant CT26 murine tumor shows high sensitivity to VA7 virotherapy: A novel system to study innate immunity and antigen dominance in oncolytic immuno-virotherapy

Project description:Recently, attenuated Semliki Forest virus vector VA7 completely eliminated type I interferon (IFN) unresponsive human U87 glioma xenografts while IFN responsive mouse GL261 and CT-2A gliomas proved refractory to the oncolytic virotherapy. Here we describe in two clones of a well established Balb/c mouse tumor cell line, CT26 murine colon carcinoma, diametrically opposed IFN responsiveness and sensitivity to oncolytic virus. Both CT26WT and CT26LacZ clones secreted biologically active type I IFN in vitro upon infection but virus replication was self-limiting only in CT26WT cells. Total transcriptome sequencing (RNA-Seq) and western blotting experiments revealed that in sharp contrast to CT26LacZ cells, CT26WT cells had strong constitutive expression of 56 different genes associated with pattern recognition and type I interferon signaling pathways, spanning two reported anti-RNA virus gene signatures and22 genes that have been reported to have direct anti-Alphaviral activity. Correspondingly, only CT26LacZ tumors were infectable in vivo, resulting in rapid central necrosis of the tumors by 96 hours post infection and complete tumor eradication both in immunocompetent and in SCID mice. CT26LacZ tumor eradication by oncolysis induced 100% protective immunity against homologous CT26LacZ challenge but only 50% protection against heterologous CT26WT challenge, indicating LacZ immune dominance over shared antigens. We believe the two clone CT26 system described herein constitutes a challenging yet realistic model for clonally and immunologically heterogeneous cancer where a strong therapy efficacy bias toward sensitive tumor subpopulations might falsely predict therapeutic success on a broad patient scale highlighting the necessity of successful pre-screening for responsive tumors. RNA-Seq in CT26 tumor cell line

2014-09-05 | E-GEOD-53001 | biostudies-arrayexpress

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