IGFBP2 Is a Potential Master Regulator Driving the Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

Only 2% of glioblastoma multiforme (GBM) patients respond to standard therapy and survive beyond 36 months (long-term survivors, LTS), while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the Gene Ontology (GO) categories “epithelial-to-mesenchymal transition” and “response to hypoxia.” In this article, we applied an upstream analysis approach that involves state-of-the-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors (TFs) associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG, and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators [insulin-like growth factor binding protein 2 (IGFBP2), vascular endothelial growth factor A (VEGFA), VEGF165, platelet-derived growth factor A (PDGFA), adipocyte enhancer-binding protein (AEBP1), and oncostatin M (OSMR)], which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. A critical analysis of this gene regulatory network gives insights into the mechanism of gene regulation by IGFBP2 via several TFs including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations were validated in independent cohorts, and their impact on overall survival has been investigated.

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IGFBP2 is a Potential Master-Regulator Driving Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

10.20944/preprints202010.0046.v2 ◽

2020 ◽

Author(s):

Manasa KP ◽

Darius Wlochowitz ◽

Edgar Wingender ◽

Tim Beißbarth ◽

ALEXANDER KEL

Keyword(s):

Transcription Factors ◽

Glioblastoma Multiforme ◽

Network Analysis ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Short Survival ◽

Tumor Invasiveness ◽

Gene Regulatory

Only two percent of Glioblastoma multiforme (GBM) patients respond to standard care and survive beyond 36 months (long-term survivors, LTS) while the majority survives less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that co-occur with aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the GO-categories “epithelial to mesenchymal transition” and “response to hypoxia”. In this paper we applied upstream analysis approach which involves state-of-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Transcription factors associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG and seven others were found enriched in regulatory regions of the dysregulated genes. Based on network analysis, we propose novel gene regulatory network regulated by five master regulators – IGFBP2, VEGFA, VEGF165, PDGFA, AEBP1 and OSMR which can potentially act as therapeutic targets for enhancing GBM prognosis. Critical analysis of this gene regulatory network gives insights on mechanism of gene regulation by IGFBP2 via several transcription factors including the key molecule of GBM tumor invasiveness and progression FRA-1. All the observations are validated in independent cohorts and their impact on overall is studied on TCGA-GBM RNA seq data.

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IGFBP2 is a Potential Master-Regulator Driving Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

10.20944/preprints202010.0046.v3 ◽

2021 ◽

Author(s):

Manasa KP ◽

Darius Wlochowitz ◽

Edgar Wingender ◽

Tim Beißbarth ◽

ALEXANDER KEL

Keyword(s):

Transcription Factors ◽

Glioblastoma Multiforme ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Short Survival ◽

Tumor Invasiveness ◽

Gene Regulatory ◽

Long Term Survivors

Only two percent of Glioblastoma multiforme (GBM) patients respond to standard care and survive beyond 36 months (long-term survivors, LTS) while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the GO-categories “epithelial to mesenchymal transition” and “response to hypoxia”. In this paper we applied upstream analysis approach which involves state-of-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators – IGFBP2, VEGFA, VEGF165, PDGFA, AEBP1 and OSMR which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. Critical analysis of this gene regulatory network gives insights on mechanism of gene regulation by IGFBP2 via several transcription factors including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations are validated in independent cohorts and their impact on overall survival is studied.

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A gene regulatory network to control EMT programs in development and disease

Nature Communications ◽

10.1038/s41467-019-13091-8 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 9

Author(s):

Hassan Fazilaty ◽

Luciano Rago ◽

Khalil Kass Youssef ◽

Oscar H. Ocaña ◽

Francisco Garcia-Asencio ◽

...

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Epithelial To Mesenchymal Transition ◽

Good Prognosis ◽

Vertebrate Development ◽

Cell Plasticity ◽

Mesenchymal Transition ◽

Gene Regulatory

Abstract The Epithelial to Mesenchymal Transition (EMT) regulates cell plasticity during embryonic development and in disease. It is dynamically orchestrated by transcription factors (EMT-TFs), including Snail, Zeb, Twist and Prrx, all activated by TGF-β among other signals. Here we find that Snail1 and Prrx1, which respectively associate with gain or loss of stem-like properties and with bad or good prognosis in cancer patients, are expressed in complementary patterns during vertebrate development and in cancer. We show that this complementarity is established through a feedback loop in which Snail1 directly represses Prrx1, and Prrx1, through direct activation of the miR-15 family, attenuates the expression of Snail1. We also describe how this gene regulatory network can establish a hierarchical temporal expression of Snail1 and Prrx1 during EMT and validate its existence in vitro and in vivo, providing a mechanism to switch and select different EMT programs with important implications in development and disease.

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Modeling a gene regulatory network of EMT hybrid states for mouse embryonic skin cells

10.1101/799908 ◽

2019 ◽

Author(s):

Dan Ramirez ◽

Vivek Kohar ◽

Ataur Katebi ◽

Mingyang Lu

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Epithelial Mesenchymal Transition ◽

Expression Patterns ◽

Mesenchymal Transition ◽

Hybrid State ◽

Regulatory Interactions ◽

Skin Cells ◽

Embryonic Skin ◽

Gene Regulatory

AbstractEpithelial-mesenchymal transition (EMT) plays a crucial role in embryonic development and tumorigenesis. Although EMT has been extensively studied with both computational and experimental methods, the gene regulatory mechanisms governing the transition are not yet well understood. Recent investigations have begun to better characterize the complex phenotypic plasticity underlying EMT using a computational systems biology approach. Here, we analyzed recently published single-cell RNA sequencing data from E9.5 to E11.5 mouse embryonic skin cells and identified the gene expression patterns of both epithelial and mesenchymal phenotypes, as well as a clear hybrid state. By integrating the scRNA-seq data and gene regulatory interactions from the literature, we constructed a gene regulatory network model governing the decision-making of EMT in the context of the developing mouse embryo. We simulated the network using a recently developed mathematical modeling method, named RACIPE, and observed three distinct phenotypic states whose gene expression patterns can be associated with the epithelial, hybrid, and mesenchymal states in the scRNA-seq data. Additionally, the model is in agreement with published results on the composition of EMT phenotypes and regulatory networks. We identified Wnt signaling as a major pathway in inducing the EMT and its role in driving cellular state transitions during embryonic development. Our findings demonstrate a new method of identifying and incorporating tissue-specific regulatory interactions into gene regulatory network modeling.Author SummaryEpithelial-mesenchymal transition (EMT) is a cellular process wherein cells become disconnected from their surroundings and acquire the ability to migrate through the body. EMT has been observed in biological contexts including development, wound healing, and cancer, yet the regulatory mechanisms underlying it are not well understood. Of particular interest is a purported hybrid state, in which cells can retain some adhesion to their surroundings but also show mesenchymal traits. Here, we examine the prevalence and composition of the hybrid state in the context of the embryonic mouse, integrating gene regulatory interactions from published experimental results as well as from the specific single cell RNA sequencing dataset of interest. Using mathematical modeling, we simulated a regulatory network based on these sources and aligned the simulated phenotypes with those in the data. We identified a hybrid EMT phenotype and revealed the inducing effect of Wnt signaling on EMT in this context. Our regulatory network construction process can be applied beyond EMT to illuminate the behavior of any biological phenomenon occurring in a specific context, allowing better identification of therapeutic targets and further research directions.

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Cooperative Signaling between Oncostatin M, Hepatocyte Growth Factor and Transforming Growth Factor-β Enhances Epithelial to Mesenchymal Transition in Lung and Pancreatic Tumor Models

Cells Tissues Organs ◽

10.1159/000320179 ◽

2010 ◽

Vol 193 (1-2) ◽

pp. 114-132 ◽

Cited By ~ 12

Author(s):

Gretchen M. Argast ◽

Peter Mercado ◽

Iain J. Mulford ◽

Matthew O’Connor ◽

David M. Keane ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Epithelial To Mesenchymal Transition ◽

Pancreatic Tumor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Oncostatin M ◽

Tumor Models ◽

Mesenchymal Transition ◽

Hepatocyte Growth

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Faculty Opinions recommendation of Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718299577.793497507 ◽

2014 ◽

Author(s):

Benjamin Feldman

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Epithelial Mesenchymal Transition ◽

Network Control ◽

Mesenchymal Transition ◽

Gene Regulatory

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Insulin-like growth factor-binding protein-3 promotes transforming growth factor-β1-mediated epithelial-to-mesenchymal transition and motility in transformed human esophageal cells

Carcinogenesis ◽

10.1093/carcin/bgq108 ◽

2010 ◽

Vol 31 (8) ◽

pp. 1344-1353 ◽

Cited By ~ 45

Author(s):

Mitsuteru Natsuizaka ◽

Shinya Ohashi ◽

Gabrielle S. Wong ◽

Azal Ahmadi ◽

Ross A. Kalman ◽

...

Keyword(s):

Growth Factor ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Binding Protein ◽

Transforming Growth Factor Β1 ◽

Insulin Like Growth Factor ◽

Mesenchymal Transition ◽

Factor Binding

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IGFBP2 is a Potential Master-Regulator Driving Dysregulated Gene Network Responsible for Short Survival in Glioblastoma Multiforme

10.20944/preprints202010.0046.v1 ◽

2020 ◽

Author(s):

Manasa KP ◽

Darius Wlochowitz ◽

Edgar Wingender ◽

Tim Beißbarth ◽

ALEXANDER KEL

Keyword(s):

Transcription Factor ◽

Glioblastoma Multiforme ◽

Poor Prognosis ◽

Gene Network ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition ◽

Short Survival ◽

Master Regulators ◽

Tumor Invasiveness ◽

Impact On Survival

Only 2% of Glioblastoma multiforme (GBM) patients respond to standard care and survive beyond 36 months (long-term survivors, LTS) while the majority survives less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that co-occur with aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the GO-categories “epithelial to mesenchymal transition” and “response to hypoxia”. Promoter and network analysis of the DEGs identified 5 potential master regulators that may explain dysregulation of the DEGs in the STS. The following 5 important master-regulators were identified: IGFBP2, VEGFA, PDGFA, OSMR and AEBP1. It is known that IGFBP2 confers increasing malignancy leading to poor prognosis. However, the molecular mechanism by which IGFBP2 affects disease progression and patient prognosis is unclear. Here we found that IGFBP2 is highly upregulated in short survivors and significantly impact survival. Further investigation of the gene regulatory network revealed that IGFBP2 expression can be regulated by FRA-1 transcription factor via MEK2/RAF/ERK5 pathway. FRA-1 is found to be upregulated and to have significant impact on survival in GBM. It is previously reported that FRA-1 can dysregulate at-least 50 genes involved in tumor invasiveness in tumor xenografts making it a therapeutic target for GBM intervention. We propose that IGFBP2 drives dysregulated gene network responsible for short survival in GBM via FRA-1 transcription factor.

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A genome-wide assessment of the ancestral neural crest gene regulatory network

10.1101/275875 ◽

2018 ◽

Cited By ~ 1

Author(s):

Dorit Hockman ◽

Vanessa Chong-Morrison ◽

Daria Gavriouchkina ◽

Stephen Green ◽

Chris T. Amemiya ◽

...

Keyword(s):

Neural Crest ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Regulatory Elements ◽

Ancestral State ◽

Enhancer Activity ◽

Mesenchymal Transition ◽

A Genome ◽

Gene Regulatory ◽

Insight Into

AbstractThe neural crest is an embryonic cell population that contributes to key vertebrate-specific features including the craniofacial skeleton and peripheral nervous system. Here we examine the transcriptional profiles and chromatin accessibility of neural crest cells in the basal sea lamprey, in order to gain insight into the ancestral state of the neural crest gene regulatory network (GRN) at the dawn of vertebrates. Transcriptome analyses reveal clusters of co-regulated genes during neural crest specification and migration that show high conservation across vertebrates for dynamic programmes like Wnt modulation during the epithelial to mesenchymal transition, but also reveal novel transcription factors and cell-adhesion molecules not previously implicated in neural crest migration. ATAC-seq analysis refines the location of known cis-regulatory elements at the Hox-α2 locus and uncovers novel cis-regulatory elements for Tfap2B and SoxE1. Moreover, cross-species deployment of lamprey elements in zebrafish reveals that the lamprey SoxE1 enhancer activity is deeply conserved, mediating homologous expression in jawed vertebrates. Together, our data provide new insight into the core elements of the GRN that are conserved to the base of the vertebrates, as well as expose elements that are unique to lampreys.

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