The Roles of EphB2 in Cancer

Liu, Wei; Yu, Chengpeng; Li, Jianfeng; Fang, Jiwei

doi:10.3389/fcell.2022.788587

Cited by 20 publications

(22 citation statements)

References 120 publications

(198 reference statements)

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“…PET1 alone did not cause phosphorylation of any RTKs, suggesting that the peptide does not cause off-target effects. We observed that after EGF treatment, EGFR was heavily phosphorylated (red) as expected, and EGFR co-receptors showed increased phosphorylation including ErbB2/Her2 (orange), ErbB3/HER3 (purple), MerTK (green), and EphB2 (yellow) (35)(36)(37). Interestingly, while EGFR phosphorylation was not sensitive to the presence of the peptide, phosphorylation of MerTK and EphB2 appeared to show a decrease with EGFR+PET1 treatment.…”

Section: Pet1 Co-localizes With and Binds To Egfrsupporting

confidence: 71%

Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions

Schuster¹,

Sahoo²,

Kim³

et al. 2022

Preprint

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The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) commonly targeted for inhibition by anti-cancer therapeutics. Current therapeutics target the kinase domain or extracellular region of EGFR. However, these types of inhibitors are not specific for tumors over healthy tissue and therefore cause undesirable side effects. Our lab has recently developed a new strategy to regulate RTK activity by designing a peptide that specifically binds to the transmembrane (TM) region of the RTK to allosterically modify kinase activity. These peptides are acidity-responsive, allowing them to preferentially target acidic environments like tumors. We have applied this strategy to EGFR and created the PET1 peptide. We observed that PET1 behaves as a pH-responsive peptide that modulates the configuration of the EGFR TM through a direct interaction. Our data indicated that PET1 inhibits EGFR-mediated cell migration. Finally, we investigated the mechanism of inhibition through molecular dynamics simulations, which showed that PET1 sits between the EGFR TM dimer. We propose that the resulting disruption of native TM interactions disrupts the conformation of the kinase domain, inhibiting the ability of EGFR to send migratory cell signals. This study is a proof-of-concept that acidity-responsive membrane peptide ligands can be generally applied to RTKs. In addition, PET1 constitutes a viable approach to therapeutically target the TM of EGFR.

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Section: Pet1 Co-localizes With and Binds To Egfrsupporting

confidence: 71%

Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions

Schuster¹,

Sahoo²,

Kim³

et al. 2022

Preprint

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show abstract

“…In hepatocellular carcinoma, EPHB2 enhances cancer stem cell properties and drive sorafenib resistance by activating SRC/AKT/GSK3β/β-catenin signaling cascade. Moreover, EPHB2 mediated malignant progression of medulloblastoma by regulating ERK, P38 and mTOR pathway ( 37 , 38 ). Although studies have shown that EPHB2 is involved in the malignant progression of various cancers, its role in LUAD has yet to be investigated ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, EPHB2 mediated malignant progression of medulloblastoma by regulating ERK, P38 and mTOR pathway ( 37 , 38 ). Although studies have shown that EPHB2 is involved in the malignant progression of various cancers, its role in LUAD has yet to be investigated ( 37 ). In the present study, we found that EPHB2 was closely associated with malignant progression of LUAD, promoting proliferation, invasion and migration of LUAD cells.…”

Section: Discussionmentioning

confidence: 99%

Prediction of prognosis, immunogenicity and efficacy of immunotherapy based on glutamine metabolism in lung adenocarcinoma

Liu

Shen

et al. 2022

Front. Immunol.

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BackgroundGlutamine (Gln) metabolism has been reported to play an essential role in cancer. However, a comprehensive analysis of its role in lung adenocarcinoma is still unavailable. This study established a novel system of quantification of Gln metabolism to predict the prognosis and immunotherapy efficacy in lung cancer. Further, the Gln metabolism in tumor microenvironment (TME) was characterized and the Gln metabolism-related genes were identified for targeted therapy.MethodsWe comprehensively evaluated the patterns of Gln metabolism in 513 patients diagnosed with lung adenocarcinoma (LUAD) based on 73 Gln metabolism-related genes. Based on differentially expressed genes (DEGs), a risk model was constructed using Cox regression and Lasso regression analysis. The prognostic efficacy of the model was validated using an individual LUAD cohort form Shandong Provincial Hospital, an integrated LUAD cohort from GEO and pan-cancer cohorts from TCGA databases. Five independent immunotherapy cohorts were used to validate the model performance in predicting immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize Gln metabolism in TME. Finally, single-cell sequencing analysis, transcriptome sequencing, and a series of in vitro experiments were used to explore the role of EPHB2 in LUAD.ResultsPatients with LUAD were eventually divided into low- and high-risk groups. Patients in low-risk group were characterized by low levels of Gln metabolism, survival advantage, “hot” immune phenotype and benefit from immunotherapy. Compared with other cells, tumor cells in TME exhibited the most active Gln metabolism. Among immune cells, tumor-infiltrating T cells exhibited the most active levels of Gln metabolism, especially CD8 T cell exhaustion and Treg suppression. EPHB2, a key gene in the model, was shown to promote LUAD cell proliferation, invasion and migration, and regulated the Gln metabolic pathway. Finally, we found that EPHB2 was highly expressed in macrophages, especially M2 macrophages. It may be involved in the M2 polarization of macrophages and mediate the negative regulation of M2 macrophages in NK cells.ConclusionThis study revealed that the Gln metabolism-based model played a significant role in predicting prognosis and immunotherapy efficacy in lung cancer. We further characterized the Gln metabolism of TME and investigated the Gln metabolism-related gene EPHB2 to provide a theoretical framework for anti-tumor strategy targeting Gln metabolism.

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“…In this study, we adopted the approach of text mining and bioinformatics, and finally, four potential genes (EPHB2, SPP1, SERPINE1, and VEGFC) were found. The erythropoietin-producing hepatocellular carcinoma receptor B2 (EPHB2), an essential member of the erythropoietin-producing hepatocellular carcinoma (EPH) receptor family, has been confirmed to be highly expressed in various tumors, such as breast cancer, meningioma, colorectal cancer, gastric cancer, and lung cancer [22]. High expression of EPHB2 is considered a proto-oncogene by promoting blood vessel formation by enhancing cancer cell motility, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

A Four-Gene Signature Associated with Radioresistance in Head and Neck Squamous Cell Carcinoma Identified by Text Mining and Data Analysis

Zhang

Wang

et al. 2022

Computational and Mathematical Methods in Medicine

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Purpose. Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer globally, and radiotherapy plays a crucial part in its treatment. This study was designed to identify potential genes related to radiation resistance in HNSCC. Method. We first used text mining to obtain common genes related to radiotherapy resistance and HNSCC in published articles. Functional enrichment analyses were conducted to identify the significantly enriched pathways and genes. Protein and protein interactions were performed, and the most significant gene modules were determined; then, genes in the gene modules were validated at transcriptional levels and overall survival. Gene set variation analysis (GSVA) score was calculated, and the association between GSVA score and survival/pathway was estimated. Immune cell infiltration, methylation, and genetic alteration analysis of these genes was conducted in HNSCC patients. Finally, potential sensitive anticancer drugs related to target genes were obtained. Result. We identified 583 common genes through text mining. After further validation, a four-gene signature (EPHB2, SPP1, SERPINE1, and VEGFC) was constructed. The patients with higher GSVA scores have a worse prognosis than those with lower GSVA scores. Differences in methylation of these four genes in HNSCC tumor tissue and normal tissue were compared, with higher methylation levels of EBPH2 and SPP1 in normal tissue and higher methylation levels of SERPINE1 in the tumor. Immune cell infiltration revealed that the increased expression of these genes was closely related to the infiltration level of CD4+ T cell, neutrophil, macrophage, and dendritic cell. Thirty drugs, including 22 positively and eight negatively correlated drugs that most correlated with related genes, were available for treating HNSCC. Conclusion. In this study, we identified four potential genes as well as corresponding drugs that might be related to radioresistance in HNSCC patients. These candidate genes may provide a promising avenue to further elevate radiotherapy efficacy.

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The Roles of EphB2 in Cancer

Cited by 20 publications

References 120 publications

Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions

Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions

Prediction of prognosis, immunogenicity and efficacy of immunotherapy based on glutamine metabolism in lung adenocarcinoma

A Four-Gene Signature Associated with Radioresistance in Head and Neck Squamous Cell Carcinoma Identified by Text Mining and Data Analysis

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