Integrative Analysis of Neuregulin Family Members-Related Tumor Microenvironment for Predicting the Prognosis in Gliomas

Zhao, Wenjin; Ou, Guan‐Yong; Lin, Wen–Jen

doi:10.3389/fimmu.2021.682415

Cited by 23 publications

(14 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transmembrane EGFR ligands comprise an N-terminal signal peptide, pro-peptide region, the EGF-lik short juxtamembrane stalk, a hydrophobic transmembrane domain, and a cytoplasmic domain ( Figure 1 A). Neuregulins (NRGs) are a family containing the EGF-like domain proteins; they play an essential role in the development of the adult brain [ 4 ] and various cancers [ 5 , 6 , 7 ]. The most studied NRGs, such as the NRG1 gene, produce six different types and 33 spliced isoforms, due to different transcriptional initiation sites and alternative splicing [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of EREG/EGFR Pathway in Tumor Progression

Cheng

Feng

Lee

et al. 2021

IJMS

109

View full text Add to dashboard Cite

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.

show abstract

Section: Introductionmentioning

confidence: 99%

The Role of EREG/EGFR Pathway in Tumor Progression

Cheng

Feng

Lee

et al. 2021

IJMS

109

View full text Add to dashboard Cite

show abstract

“…Recently, a large scale of bioinformatics studies utilized public data resources to identify glioma prognostic signatures, including gene signatures ( 35 – 40 ), lncRNA signature ( 41 ), and gene-set signature ( 42 , 43 ). The summary of all of these prognostic studies and our study was displayed in Table S4 .…”

Section: Discussionmentioning

confidence: 99%

“…( 38 ) constructed a 6-gene risk model based on glioma samples from TCGA and validated it using CGGA samples. Some other studies performed the survival analysis based on some key genes or gene sets without identifying signature procedures ( 39 , 42 ). Regarding both the construction and validation of the prognostic model, an adequate number of the training set and testing set were necessary for a robust risk model analysis.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Features of the Tumor Immune Microenvironment in Glioma and Their Clinical Applications: Analysis of Multiple Cohorts

Zhang

Tan

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Glioma is the most common malignant tumor of the central nervous system. Tumor purity is a source of important prognostic factor for glioma patients, showing the key roles of the microenvironment in glioma prognosis. In this study, we systematically screened functional characterization related to the tumor immune microenvironment and constructed a risk model named Glioma MicroEnvironment Functional Signature (GMEFS) based on eight cohorts. The prognostic value of the GMEFS model was also verified in another two glioma cohorts, glioblastoma (GBM) and low-grade glioma (LGG) cohorts, from The Cancer Genome Atlas (TCGA). Nomograms were established in the training and testing cohorts to validate the clinical use of this model. Furthermore, the relationships between the risk score, intrinsic molecular subtypes, tumor purity, and tumor-infiltrating immune cell abundance were also evaluated. Meanwhile, the performance of the GMEFS model in glioma formation and glioma recurrence was systematically analyzed based on 16 glioma cohorts from the Gene Expression Omnibus (GEO) database. Based on multiple-cohort integrated analysis, risk subpathway signatures were identified, and a drug–subpathway association network was further constructed to explore candidate therapy target regions. Three subpathways derived from Focal adhesion (path: 04510) were identified and contained known targets including platelet derived growth factor receptor alpha (PDGFRA), epidermal growth factor receptor (EGFR), and erb-b2 receptor tyrosine kinase 2 (ERBB2). In conclusion, the novel functional signatures identified in this study could serve as a robust prognostic biomarker, and this study provided a framework to identify candidate therapeutic target regions, which further guide glioma patients’ clinical decision.

show abstract

“…MGMT promoter methylation status is considered a prognostic marker that helps to decide treatment (31). Further characterization of LGG biomarkers that might define clinical pand guide patient treatment can be achieved by assessing the transcriptomic landscape of individual tumors (32)(33)(34)(35)(36)(37). In this regard, considering that signaling circuits might be postulated as oncogenic signatures whose characterization as integrated networks, composed by a repertoire of receptors, transducers, and effectors, might be indicative of vulnerabilities and prognosis, here we pursued a systematic data-mining strategy aimed to characterize the repertoire of P-Rex1-linked signaling proteins that correlate with bad prognosis of LGG patients.…”

Section: Introductionmentioning

confidence: 99%

P-Rex1 Signaling Hub in Lower Grade Glioma Patients, Found by In Silico Data Mining, Correlates With Reduced Survival and Augmented Immune Tumor Microenvironment

2022

View full text Add to dashboard Cite

Systematic analysis of tumor transcriptomes, combined with deep genome sequencing and detailed clinical assessment of hundreds of patients, constitutes a powerful strategy aimed to identify potential biomarkers and therapeutic targets to guide personalized treatments. Oncogenic signaling cascades are integrated by multidomain effector proteins such as P-Rex1, a guanine nucleotide exchange factor for the Rac GTPase (RacGEF), known to promote metastatic dissemination of cancer cells. We hypothesized that patients with high P-Rex1 expression and reduced survival might be characterized by a particular set of signaling proteins co-expressed with this effector of cell migration as a central component of a putative signaling hub indicative of poor prognosis. High P-Rex1 expression correlated with reduced survival of TCGA Lower Grade Glioma (LGG) patients. Thus, guided by PREX1 expression, we searched for signaling partners of this RacGEF by applying a systematic unbiased in silico data mining strategy. We identified 30 putative signaling partners that also correlated with reduced patient survival. These included GPCRs such as CXCR3, GPR82, FZD6, as well as MAP3K1, MAP2K3, NEK8, DYRK3 and RPS6KA3 kinases, and PTPN2 and PTPN22 phosphatases, among other transcripts of signaling proteins and phospho-substrates. This PREX1 signaling hub signature correlated with increased risk of shorter survival of LGG patients from independent datasets and coincided with immune and endothelial transcriptomic signatures, indicating that myeloid infiltration and tumor angiogenesis might contribute to worsen brain tumor pathology. In conclusion, P-Rex1 and its putative signaling partners in LGG are indicative of a signaling landscape of the tumor microenvironment that correlates with poor prognosis and might guide the characterization of signaling targets leading the eventual development of immunotherapeutic strategies.

show abstract

Integrative Analysis of Neuregulin Family Members-Related Tumor Microenvironment for Predicting the Prognosis in Gliomas

Cited by 23 publications

References 60 publications

The Role of EREG/EGFR Pathway in Tumor Progression

The Role of EREG/EGFR Pathway in Tumor Progression

Prognostic Features of the Tumor Immune Microenvironment in Glioma and Their Clinical Applications: Analysis of Multiple Cohorts

P-Rex1 Signaling Hub in Lower Grade Glioma Patients, Found by In Silico Data Mining, Correlates With Reduced Survival and Augmented Immune Tumor Microenvironment

Contact Info

Product

Resources

About