scholarly journals Pan-Cancer Analysis Shows Enrichment of Macrophages, Overexpression of Checkpoint Molecules, Inhibitory Cytokines, and Immune Exhaustion Signatures in EMT-High Tumors

2022 ◽  
Vol 11 ◽  
Author(s):  
Jayesh Kumar Tiwari ◽  
Shloka Negi ◽  
Manju Kashyap ◽  
Sheikh Nizamuddin ◽  
Amar Singh ◽  
...  

Epithelial–mesenchymal transition (EMT) is a highly dynamic process that occurs under normal circumstances; however, EMT is also known to play a central role in tumor progression and metastasis. Furthermore, role of tumor immune microenvironment (TIME) in shaping anticancer immunity and inducing the EMT is also well recognized. Understanding the key features of EMT is critical for the development of effective therapeutic interventions. Given the central role of EMT in immune escape and cancer progression and treatment, we have carried out a pan-cancer TIME analysis of The Cancer Genome Atlas (TCGA) dataset in context to EMT. We have analyzed infiltration of various immune cells, expression of multiple checkpoint molecules and cytokines, and inflammatory and immune exhaustion gene signatures in 22 cancer types from TCGA dataset. A total of 16 cancer types showed a significantly increased (p < 0.001) infiltration of macrophages in EMT-high tumors (mesenchymal samples). Furthermore, out of the 17 checkpoint molecules we analyzed, 11 showed a significant overexpression (p < 0.001) in EMT-high samples of at least 10 cancer types. Analysis of cytokines showed significant enrichment of immunosuppressive cytokines—TGFB1 and IL10—in the EMT-high group of almost all cancer types. Analysis of various gene signatures showed enrichment of inflammation, exhausted CD8+ T cells, and activated stroma signatures in EMT-high tumors. In summary, our pan-cancer EMT analysis of TCGA dataset shows that the TIME of EMT-high tumors is highly immunosuppressive compared to the EMT-low (epithelial) tumors. The distinctive features of EMT-high tumors are as follows: (i) the enrichment of tumor-associated macrophages, (ii) overexpression of immune checkpoint molecules, (iii) upregulation of immune inhibitory cytokines TGFB1 and IL10, and (iv) enrichment of inflammatory and exhausted CD8+ T-cell signatures. Our study shows that TIMEs of different EMT groups differ significantly, and this would pave the way for future studies analyzing and targeting the TIME regulators for anticancer immunotherapy.

2020 ◽  
Vol 21 (17) ◽  
pp. 6087
Author(s):  
Yunzhen Wei ◽  
Limeng Zhou ◽  
Yingzhang Huang ◽  
Dianjing Guo

Long noncoding RNA (lncRNA)/microRNA(miRNA)/mRNA triplets contribute to cancer biology. However, identifying significative triplets remains a major challenge for cancer research. The dynamic changes among factors of the triplets have been less understood. Here, by integrating target information and expression datasets, we proposed a novel computational framework to identify the triplets termed as “lncRNA-perturbated triplets”. We applied the framework to five cancer datasets in The Cancer Genome Atlas (TCGA) project and identified 109 triplets. We showed that the paired miRNAs and mRNAs were widely perturbated by lncRNAs in different cancer types. LncRNA perturbators and lncRNA-perturbated mRNAs showed significantly higher evolutionary conservation than other lncRNAs and mRNAs. Importantly, the lncRNA-perturbated triplets exhibited high cancer specificity. The pan-cancer perturbator OIP5-AS1 had higher expression level than that of the cancer-specific perturbators. These lncRNA perturbators were significantly enriched in known cancer-related pathways. Furthermore, among the 25 lncRNA in the 109 triplets, lncRNA SNHG7 was identified as a stable potential biomarker in lung adenocarcinoma (LUAD) by combining the TCGA dataset and two independent GEO datasets. Results from cell transfection also indicated that overexpression of lncRNA SNHG7 and TUG1 enhanced the expression of the corresponding mRNA PNMA2 and CDC7 in LUAD. Our study provides a systematic dissection of lncRNA-perturbated triplets and facilitates our understanding of the molecular roles of lncRNAs in cancers.


2018 ◽  
Author(s):  
Lingjian Yang ◽  
Laura Forker ◽  
Christina S. Fjeldbo ◽  
Robert G. Bristow ◽  
Heidi Lyng ◽  
...  

ABSTRACTHypoxia is a generic micro-environmental factor in most solid tumours. While most published literature focused on in vitro or single tumour type investigations, we carried out the first multi-omics pan cancer analysis of hypoxia with the aim of gaining a comprehensive understanding of its implication in tumour biology. A core set of 52 mRNAs were curated based on experimentally validated hypoxia gene sets from multiple cancer types. The 52 mRNAs collectively stratified high- and low-hypoxia tumours from The Cancer Genome Atlas (TCGA) database (9698 primary tumours) in each of the 32 cancer types available. High- hypoxia tumours had high expression of not only mRNA but also protein and microRNA markers of hypoxia. In a pan cancer transcriptomic analysis, ≥70% of the known cancer hallmark pathways were enriched in high-hypoxia tumours, most notably epithelial mesenchymal transition potential, proliferation (G2M checkpoint, E2F targets, MYC targets) and immunology response. In a multi-omics analysis, gene expression-determined high- hypoxia tumours had a higher non-silent mutation rate, DNA damage repair deficiency and leukocyte infiltration. The associations largely remained significant after correcting for confounding factors, showing a profound impact of hypoxia in tumour evolution across cancer types. High-hypoxia tumours determined using the core gene set had a poor prognosis in 16/32 cancer types, with statistical significances remaining in five after adjusting for tumour stage and omics biomarkers. In summary, this first comprehensive in vivo map of hypoxia in cancers highlights the importance of this micro-environmental factor in driving tumour progression.


Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 235
Author(s):  
Wei Feng Ma ◽  
Howard E. Boudreau ◽  
Thomas L. Leto

Previously, we have shown TGF-β-induced NOX4 expression is involved in the epithelial-to-mesenchymal transition (EMT), a process critical for cancer metastasis, and that wild-type (WT) and mutant (Mut) p53 have divergent effects on TGF-β induction of NOX4: WT-p53 suppresses whereas Mut-p53 augments NOX4 mRNA and protein production in several tumor cell models. We sought to validate and extend our model by analyzing whole-exome data of primary tumor samples in The Cancer Genome Atlas (TCGA). We constructed a Pan-Cancer dataset from 23 tumor types and explored NOX4 expression patterns in relation to EMT and patient survival. NOX4 mRNA levels increase as a function of cancer progression in several cancers and correlate with Mut-p53 mRNA and genes involved in programs of EMT, cellular adhesion, migration, and angiogenesis. Tumor macrophages appear to be a source of NOX2, whose association with genetic programs of cancer progression emulate that of NOX4. Notably, increased NOX4 expression is linked to poorer survival in patients with Mut-TP53, but better survival in patients with WT-TP53. NOX4 is negatively associated with markers of apoptosis and positively with markers of proliferation in patients with Mut-TP53, consistent with their poorer survival. These findings suggest that TP53 mutations could “switch” NOX4 from being protective and an indicator of good prognosis to deleterious by promoting programs favoring cancer progression.


2020 ◽  
Author(s):  
Jinfang Cui ◽  
Yang Song ◽  
Xuejiao Han ◽  
Jing Hu ◽  
Yanbo Chen ◽  
...  

Abstract Background: 14-3-3ζ protein which acts as a putative oncoprotein has been found to promote proliferation, metastasis and chemoresistance of cancer cells in several cancers including lung adenocarcinoma (LUAD), however, its significance in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance remains unknown. Methods: The Cancer Genome Atlas (TCGA) database was used to determine 14-3-3ζ expression in pan-cancer and LUAD. 14-3-3ζ and ID1 expression was then examined in clinical LUAD samples by immunohistochemistry (IHC). Lentiviral transfection with 14-3-3ζ-specific shRNA was used to establish stable 14-3-3ζ knockdown gefitinib resistant PC9 (PC9/GR) and H1975 cell lines. The effect of 14-3-3ζ knockdown on reversing EGFR-TKI resistance was determined in vitro by CCK-8, wound healing, transwell assays and flow cytometry. A xenograft tumor model was established to evaluate the role of 14-3-3ζ in EGFR-TKI resistance. Microarray analysis results showed the multiple pathways regulated by 14-3-3ζ-shRNA. Results: In the present study, we firstly demonstrated that 14-3-3ζ expression was elevated and predicted unfavourable prognosis in pan-cancer including LUAD based on TCGA. In addition, high 14-3-3ζ expression was significantly associated with advanced T stage, TNM stage, present of lymph node metastasis and, importantly, poor treatment response to EGFR-TKI in LUAD patients with EGFR-activating mutations. 14-3-3ζ shRNA significantly sensitized EGFR-TKI-resistant human LUAD cells to gefitinib and, notably, reversed epithelial-to-mesenchymal transition (EMT). BMP signaling activation was decreased in EGFR-TKI resistant cells followed by 14-3-3ζ depletion in microarray analysis, which was further validated by Western blot analysis. Furthermore, the expression of 14-3-3ζ positively correlates with ID1 expression in human EGFR-mutant LUAD patient samples. In vivo , 14-3-3ζ shRNA and gefitinib treatment resulted in a significant reduction in the tumor burden compared to that treated with gefitinib alone. Conclusion: Our work uncovers a hitherto unappreciated role of 14-3-3ζ in EGFR-TKI resistance. This study might provide a potential therapeutic approach for treating LUAD patients harboring EGFR mutations.


2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Tianyu Zheng ◽  
Xindong Wang ◽  
Peipei Yue ◽  
Tongtong Han ◽  
Yue Hu ◽  
...  

Objective. To investigate the expression patterns and prognostic characteristics of inflammasome-related genes (IRGs) across cancer types and develop a robust biomarker for the prognosis of KIRC. Methods. The differentially expressed IRGs and prognostic genes among 10 cancers were analyzed based on The Cancer Genome Atlas (TCGA) dataset. Subsequently, an IRGs risk signature was developed in KIRC. Its prognostic accuracy was evaluated by receiver operating characteristic (ROC) analysis. The independent predictive capacity was identified by stratification survival and multivariate Cox analyses. The gene ontology (GO) analysis and principal component analysis (PCA) were performed to explore biological functions of the IRGs signature in KIRC. Results. The expression patterns and prognostic association of IRGs varied from different cancers, while KIRC showed the most abundant survival-related dysregulated IRGs. The IRG signature for KIRC was able to independently predict survival, and the signature genes were mainly involved inimmune-related processes. Conclusions. The pan-cancer analysis provided a comprehensive landscape of IRGs across cancer types and identified a strong association between IRGs and the prognosis of KIRC. Further IRGs signature represented a reliable prognostic predictor for KIRC and verified the prognostic value of inflammasomes in KIRC, contributing to our understanding of therapies targeting inflammasomes for human cancers.


2020 ◽  
Vol 124 (1) ◽  
pp. 259-269
Author(s):  
Suhas V. Vasaikar ◽  
Abhijeet P. Deshmukh ◽  
Petra den Hollander ◽  
Sridevi Addanki ◽  
Nick Allen Kuburich ◽  
...  

Abstract Background The epithelial-mesenchymal transition (EMT) enables dissociation of tumour cells from the primary tumour mass, invasion through the extracellular matrix, intravasation into blood vessels and colonisation of distant organs. Cells that revert to the epithelial state via the mesenchymal-epithelial transition cause metastases, the primary cause of death in cancer patients. EMT also empowers cancer cells with stem-cell properties and induces resistance to chemotherapeutic drugs. Understanding the driving factors of EMT is critical for the development of effective therapeutic interventions. Methods This manuscript describes the generation of a database containing EMT gene signatures derived from cell lines, patient-derived xenografts and patient studies across cancer types and multiomics data and the creation of a web-based portal to provide a comprehensive analysis resource. Results EMTome incorporates (i) EMT gene signatures; (ii) EMT-related genes with multiomics features across different cancer types; (iii) interactomes of EMT-related genes (miRNAs, transcription factors, and proteins); (iv) immune profiles identified from The Cancer Genome Atlas (TCGA) cohorts by exploring transcriptomics, epigenomics, and proteomics, and drug sensitivity and (iv) clinical outcomes of cancer cohorts linked to EMT gene signatures. Conclusion The web-based EMTome portal is a resource for primary and metastatic tumour research publicly available at www.emtome.org.


2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Guangyu Wang ◽  
Dandan Xu ◽  
Zicheng Zhang ◽  
Xinhui Li ◽  
Jiaqi Shi ◽  
...  

AbstractAn emerging body of evidence has recently recognized the coexistence of epithelial-mesenchymal transition (EMT) and immune response. However, a systems-level view and survey of the interplay between EMT and immune escape program, and their impact on tumor behavior and clinical outcome across various types of cancer is lacking. Here, we performed comprehensive multi-omics analyses to characterize the landscape of crosstalk between EMT and immune evasion and their clinical relevance across 17 types of solid cancer. Our study showed the presence of complex and dynamic immunomodulatory crosstalk between EMT and immune evasion shared by pan-cancer, and the crosstalk was significantly associated with cancer prognosis and immunotherapy response. Integrative quantitative analyses of genomics and immunogenomics revealed that cellular composition of immune infiltrates, non-synonymous mutation burden, chromosomal instability and oncogenic gene alterations are associated with the balance between EMT and immune evasion. Finally, we proposed a scoring model termed EMT-CYT Index (ECI) to quantify the EMT-immunity axis, which was a superior predictor of prognosis and immunotherapy response across different malignancies. By providing a systematic overview of crosstalk between EMT and immune evasion, our study highlights the potential of pan-cancer EMT-immunity crosstalk as a paradigm for dissecting molecular mechanisms underlying cancer progression and guiding more effective and generalized immunotherapy strategies.


2021 ◽  
Vol 11 ◽  
Author(s):  
Zheng Zhang ◽  
Shuangshuang Zhao ◽  
Haizhen Yang ◽  
Yanwei Chen ◽  
Huahui Feng ◽  
...  

Despite accumulating cell- or animal-based experiments providing the relationship between Gasdermin E (GSDME) and human diseases, especially in malignant cancers, no pan-cancer analysis about the function of GSMDE in cancer management can be available up to date. Our research, for the first time, explored the potential carcinogenic role of GSDME across 33 tumors from the public platform of TCGA (The cancer genome atlas) database. GSDME is highly expressed in most malignant cancers, and obvious relationship exists between GSDME level and survival prognosis of cancer patients. The expression of GSDME was statically associated with the cancer-associated fibroblast infiltration in diverse cancer types, such as BLCA, CHOL, GBM, KIRC, LIHC, MESO, STAD, and UCEC. Furthermore, pyroptosis, sensory perception of sound, and defense response to bacterium were involved in the functional mechanisms of GSDME expression from GO analysis. Last but not the least, in vitro experiments were also performed to identify GSDME-induced pyroptosis. Our first pan-cancer analysis of GSDME not only broadens the understanding of the carcinogenic roles of GSDME but also provides a promising therapeutic strategy for benefiting an increasing number of cancerous patients based on GSDME-induced pyroptosis.


2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Biao Wu ◽  
Yumeng Wu ◽  
Xianlin Guo ◽  
Yanping Yue ◽  
Yuanyuan Li ◽  
...  

Several studies have suggested that coatomer protein complex subunit beta 2 (COPB2) may act as an oncogene in various cancer types. However, no systematic pan-cancer analysis has been performed to date. Therefore, the present study analyzed the potential oncogenic role of COPB2 using TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) datasets. The majority of the cancer types overexpressed the COPB2 protein, and its expression significantly correlated with tumor prognosis. In certain tumors, such as those found in breast and ovarian tissues, phosphorylated S859 exhibited high expression. It was found that mutations of the COPB2 protein in kidney and endometrial cancers exhibited a significant impact on patient prognosis. It is interesting to note that COPB2 expression correlated with the number of cancer-associated fibroblasts in certain tumors, such as cervical and endocervical cancers and colon adenocarcinomas. In addition, COPB2 was involved in the transport of substances and correlated with chemotherapy sensitivity. This is considered the first pan-tumor study, which provided a relatively comprehensive understanding of the mechanism by which COPB2 promotes cancer growth.


2021 ◽  
Vol 8 ◽  
Author(s):  
Jinguo Zhang ◽  
Jian Chen ◽  
Benjie Shan ◽  
Lin Lin ◽  
Jie Dong ◽  
...  

The soluble resistance-related calcium-binding protein (sorcin, SRI) serves as the calcium-binding protein for the regulation of calcium homeostasis and multidrug resistance. Although the mounting evidence suggests a crucial role of SRI in the chemotherapeutic resistance of certain types of tumors, insights into pan-cancer analysis of SRI are unavailable. Therefore, this study aimed to probe the multifaceted properties of SRI across the 33 cancer types. The SRI expression was analyzed via The Cancer Genome Atlas (TCGA) and Genotype Tissue-Expression (GTEX) database. The SRI genomic alterations and drug sensitivity analysis were performed based on the cBioPortal and the CellMiner database. Furthermore, the correlations among the SRI expression and survival outcomes, clinical features, stemness, tumor mutation burden (TMB), microsatellite instability (MSI), and immune cells infiltration were analyzed using TCGA data. The differential analysis showed that SRI was upregulated in 25 tumor types compared with the normal tissues. Aberrant expression of SRI was able to predict survival in different cancers. Further, the most frequent alteration of SRI genomic was amplification. Moreover, the aberrant SRI expression was related to stemness score, epithelial-mesenchymal-transition (EMT)-related genes, MSI, TMB, and tumor immune microenvironment in various types of cancer. TIMER database mining further found that the SRI expression was significantly correlated with the infiltration levels of various immune cells in certain types of cancer. Intriguingly, the SRI expression was negatively correlated with drug sensitivity of fluorouracil, paclitaxel, docetaxel, and isotretinoin. Our findings highlight the predictive value of SRI in cancer and provide insights for illustrating the role of SRI in tumorigenesis and drug resistance.


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