Association Between High Immune Activity and Worse Prognosis in Uveal Melanoma and Low-Grade Glioma in TCGA Transcriptomic Data

Abstract Background: Immune status in the tumor microenvironment is an important determinant of cancer progression and patient prognosis. Although a higher immune activity is often associated with a better prognosis, this trend is not absolute and differs across cancer types. We aimed to give insights into why some cancers do not show better survival despite higher immunity by assessing the relationship between different biological factors, including cytotoxicity, and patient prognosis in various cancer types using RNA-seq data collected by The Cancer Genome Atlas.Results: Results showed that a higher immune activity was associated with worse prognosis in patients with uveal melanoma and low-grade glioma, which are cancers of immune-privileged sites. In these cancers, epithelial or endothelial mesenchymal transition and inflammatory state as well as immune activation had notably negative correlation with patient prognosis. Further analysis using additional single-cell data of uveal melanoma and glioma revealed that epithelial or endothelial mesenchymal transition was mainly induced in retinal pigment cells or endothelial cells that comprise the blood-retinal and blood-brain barriers, which are unique structures of the eye and central nervous system, respectively. Inflammation was mainly promoted by macrophages, and their infiltration increased significantly in response to immune activation. Furthermore, we found the expression of CCL5 was strongly correlated with immune activity and associated with bad prognosis, particularly in these cancers, suggesting that CCL5 is a potential molecular target for therapeutics.Conclusions: Epithelial or endothelial mesenchymal transition is associated with a bad prognosis. This suggests that inflammation loosens the structures of the blood barrier and causes further infiltration of immune cells, which may result in a feedback loop of additional inflammatory effects leading to runaway conditions.

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Elevated TYROBP expression predicts poor prognosis and high tumor immune infiltration in patients with low-grade glioma

BMC Cancer ◽

10.1186/s12885-021-08456-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiajie Lu ◽

Yuecheng Peng ◽

Rihong Huang ◽

Zejia Feng ◽

Yongyang Fan ◽

...

Keyword(s):

Dendritic Cells ◽

Signaling Pathway ◽

Low Grade Glioma ◽

Gene Set Enrichment Analysis ◽

Low Grade ◽

Ppi Network ◽

Myeloid Dendritic Cells ◽

Immune Infiltration ◽

Normal Tissues ◽

Worse Prognosis

Abstract Background Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG). Methods The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. Results Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. Conclusion TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

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Pan-Cancer Analysis Reveals Distinct Metabolic Reprogramming in Different Epithelial–Mesenchymal Transition Activity States

Cancers ◽

10.3390/cancers13081778 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1778

Author(s):

Ji-Yong Sung ◽

Jae-Ho Cheong

Keyword(s):

Energy Metabolism ◽

Epithelial Mesenchymal Transition ◽

Metabolic Reprogramming ◽

The Cancer Genome Atlas ◽

Cancer Type ◽

Mesenchymal Transition ◽

Significant Difference ◽

Cancer Types ◽

Using Data ◽

Patient Prognosis

Epithelial–mesenchymal transition (EMT) is critical for cancer development, invasion, and metastasis. Its activity influences metabolic reprogramming, tumor aggressiveness, and patient survival. Abnormal tumor metabolism has been identified as a cancer hallmark and is considered a potential therapeutic target. We profiled distinct metabolic signatures by EMT activity using data from 9452 transcriptomes across 31 different cancer types from The Cancer Genome Atlas. Our results demonstrated that ~80 to 90% of cancer types had high carbohydrate and energy metabolism, which were associated with the high EMT group. Notably, among the distinct EMT activities, metabolic reprogramming in different immune microenvironments was correlated with patient prognosis. Nine cancer types showed a significant difference in survival with the presence of high EMT activity. Stomach cancer showed elevated energy metabolism and was associated with an unfavorable prognosis (p < 0.0068) coupled with high expression of CHST14, indicating that it may serve as a potential drug target. Our analyses highlight the prevalence of cancer type-dependent EMT and metabolic reprogramming activities and identified metabolism-associated genes that may serve as potential therapeutic targets.

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A stroma-corrected ZEB1 transcriptional signature is inversely associated with antitumor immune activity in breast cancer

Scientific Reports ◽

10.1038/s41598-019-54282-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

C. James Block ◽

Gregory Dyson ◽

Ion John Campeanu ◽

Donovan Watza ◽

Manohar Ratnam ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Developmental Process ◽

Experimental Models ◽

Breast Cancer Patients ◽

Multiple Cancer ◽

Mesenchymal Transition ◽

Immune Activity ◽

Transcriptional Signature ◽

Cancer Types

AbstractThe epithelial-to-mesenchymal transition (EMT) is an essential developmental process which can be hijacked by cancer cells, leading to enhanced metastasis and chemoresistance in experimental models. Recent studies have linked gene expression of EMT-associated gene signatures to increased inflammatory immune response in multiple cancer types. However, these studies did not account for the potential confounding effects of gene expression by tumor-infiltrating mesenchymal stromal cells. In this study, we comprehensively dissect the associations between multiple EMT transcription factors and EMT markers with stromal and immune tumor infiltration. We find that EMT-related genes are highly correlated with intratumoral stromal cell abundance and identify a specific relationship between stroma-corrected ZEB1 expression and decreased immune activity in multiple cancer types. We derive a stroma-corrected ZEB1-activated transcriptional signature and demonstrate that this signature includes several known inhibitors of inflammation, including BMPR2. Finally, multivariate survival analysis reveals that ZEB1 and its expression signature are significantly associated with reduced overall survival in breast cancer patients. In conclusion, this study identifies a novel association between stroma-adjusted ZEB1 expression and tumor immune activity and addresses the critical issue of confounding between EMT-associated genes and tumor stromal content.

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Elevated TYROBP expression predicts poor prognosis and high tumor immune infiltration in patients with low‑grade glioma

10.21203/rs.3.rs-376032/v1 ◽

2021 ◽

Author(s):

Jiajie Lu ◽

Yuecheng Peng ◽

Rihong Huang ◽

Zejia Feng ◽

Yongyang Fan ◽

...

Keyword(s):

Dendritic Cells ◽

Signaling Pathway ◽

Low Grade Glioma ◽

Gene Set Enrichment Analysis ◽

Low Grade ◽

Ppi Network ◽

Myeloid Dendritic Cells ◽

Immune Infiltration ◽

Normal Tissues ◽

Worse Prognosis

Abstract Background: Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low‑grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low‑grade glioma (LGG).Methods: The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. Results: Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. Conclusion: TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

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Activity of Wnt/PCP Regulation Pathway Classifies Patients of Low-Grade Glioma Into Molecularly Distinct Subgroups With Prognostic Difference

Frontiers in Oncology ◽

10.3389/fonc.2021.726034 ◽

2021 ◽

Vol 11 ◽

Author(s):

Meng Zhang ◽

Dan Wang ◽

Lan Su ◽

Jingjiao Ma ◽

Sizhen Wang ◽

...

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Planar Cell Polarity ◽

Epithelial Mesenchymal Transition ◽

Wnt Signaling Pathway ◽

Low Grade Glioma ◽

Low Grade ◽

Aberrant Expression ◽

Mesenchymal Transition ◽

Oncology Research

Wingless/Int-1 (Wnt) signaling is one of the most well-known oncogenic pathways. Numerous studies have uncovered an aberrant expression of Wnt in cancer and its association with multiple oncogenic processes, such as cell proliferation, epithelial–mesenchymal transition (EMT), and invasiveness. Most previous studies mainly focused on the canonical branch of Wnt signaling pathway, i.e., Wnt/β-catenin signaling. The Wnt/planar cell polarity (PCP) signaling pathway, as the most recently described branch of Wnt signaling, was much less investigated in oncology research. In this study, we thoroughly characterized the activity of the Wnt/PCP regulation pathway in low-grade glioma (LGG) patients. Subtyping based on the expression pattern of the Wnt/PCP regulation pathway revealed three (C1–C3) subgroups with significant survival differences. Each group displayed distinct genomic characteristics. For instance, C1 was enriched with capicua transcriptional repressor (CIC) truncating mutations and 1p19q codel. C2 was characterized with tumor protein p53 (TP53) and ATRX chromatin remodeler (ATRX) inactivating mutations but depletion of telomerase reverse transcriptase (TERT) promoter mutations. C3 showed elevated malignancy reflected from several oncogenic characteristics, such as tumor heterogeneity and cell stemness, and demonstrated the worst survival outcome. In addition, C3 showed elevated macrophage segregation via induction of cytokines that are able to enhance the permeability of the brain–blood barrier (BBB). Lastly, we developed a prognostic model based on the risk score system. Validation indicated that our model can independently predict the prognosis of LGG patients.

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