An integrated model of acinar to ductal metaplasia-related N7-methyladenosine regulators predicts prognosis and immunotherapy in pancreatic carcinoma based on digital spatial profiling

Yang, Hao; Messina-Pacheco, Julia; Corredor, Andrea Liliam Gomez; Gregorieff, Alex; Nehme, Ali; Najafabadi, Hamed S.; Riazalhosseini, Yasser; Gao, Bo; Gao, Zu–Hua

doi:10.3389/fimmu.2022.961457

Cited by 19 publications

(23 citation statements)

References 58 publications

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“…The m7G modifications are involved in gene regulation and tumor development [ 33 ]. Over- or under-expression of m7G regulators can alter m7G modifications in tumors and affect tumor progression [ 34 ]. Therefore, for treatment and patient prognosis of early tumor diagnosis, it is essential to study the molecular processes of m7G modification and to identify aberrant expression of m7G regulators in clinical, surgical specimens.…”

Section: Discussionmentioning

confidence: 99%

N7-methylguanosin regulators-mediated methylation modification patterns and characterization of the immune microenvironment in lower-grade glioma

et al. 2023

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N7-methylguanosine (m7G) modification signature has recently emerged as a crucial regulator of tumor progression and treatment in cancer. However, there is limited information available on the genomic profile of lower-grade gliomas (LGGs) related to m7G methylation modification genes’ function in tumorigenesis and progression. In this study, we employed bioinformatics methods to characterize m7G modifications in individuals with LGG from The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). We used gene set enrichment analysis (GSEA), single sample GSEA (ssGSEA), CIBERSORT algorithm, ESTIMATE algorithm, and TIDE to evaluate the association between m7G modification patterns, tumor microenvironment (TME) cell infiltration properties, and immune infiltration markers. The m7G scoring scheme using principal component analysis (PCA) was employed to investigate the m7G modification patterns quantitatively. We examined the m7G modification hub genes' expression levels in normal samples, refractory epilepsy samples, and LGG samples using immunohistochemistry, western-blotting, and qRT-PCR. Our findings revealed that individuals with LGG could be categorized into two groups based on m7G scores (high and low) according to the properties of m7G. Moreover, we observed that high m7G score was associated with significant clinical benefit and prolonged survival duration in the anti-PD-1 cohort, while low m7G score was associated with improved prognostic outcomes and increased likelihood of complete or partial response in the anti-PD-L1 cohort. Different m7G subtypes also showed varying Tumor Mutational Burden (TMB) and immune profiles and might have distinct responses to immunotherapy. Furthermore, we identified five potential genetic markers that were highly correlated with the m7G score signature index. These findings provide insight into the features and classification associated with m7G methylation modifications and may aid in improving the clinical outcome of LGG.

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Section: Discussionmentioning

confidence: 99%

N7-methylguanosin regulators-mediated methylation modification patterns and characterization of the immune microenvironment in lower-grade glioma

et al. 2023

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“…This may be driven by increased AP-1 signalling, resulting in increased expression of PD-L1 and PD-L2 (Figure 5b) (45), which promotes macrophage polarization to an M2 type in the decidua and subsequent immunosuppression (82)(83)(84). Fibronectin and ITGβ1 also inhibit T cell activation and upregulate macrophages (91). This suggests AP-1 signalling of PD-1 and its ligands creates an immune suppressed state in PAS, which may allow EVTs to escape some of the normal immune regulators of EVT invasion.…”

Section: Discussionmentioning

confidence: 99%

Spatial proteomics and transcriptomics of placenta accreta spectrum

Bartels,

Hameed,

Young

et al. 2024

Preprint

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In severe Placenta Accreta Spectrum (PAS), trophoblasts gain deep access in the myometrium (placenta increta). This study investigated alterations at the fetal-maternal interface in PAS cases using a systems biology approach consisting of immunohistochemistry, spatial transcriptomics and proteomics. We identified spatial variation in the distribution of CD4+, CD3+and CD8+T-cells at the maternal-interface in placenta increta cases. Spatial transcriptomics identified transcription factors involved in promotion of trophoblast invasion such as AP-1 subunits ATF-3 and JUN, and NFKB were upregulated in regions with deep myometrial invasion. Pathway analysis of differentially expressed genes demonstrated that degradation of extracellular matrix (ECM) and class 1 MHC protein were increased in increta regions, suggesting local tissue injury and immune suppression. Spatial proteomics demonstrated that increta regions were characterised by excessive trophoblastic proliferation in an immunosuppressive environment. Expression of inhibitors of apoptosis such as BCL-2 and fibronectin were increased, while CTLA-4 was decreased and increased expression of PD-L1, PD-L2 and CD14 macrophages. Additionally, CD44, which is a ligand of fibronectin that promotes trophoblast invasion and cell adhesion was also increased in increta regions. We subsequently examined ligand receptor interactions enriched in increta regions, with interactions with ITGβ1, including with fibronectin and ADAMS, emerging as central in increta. These ITGβ1 ligand interactions are involved in activation of epithelial–mesenchymal transition and remodelling of ECM suggesting a more invasive trophoblast phenotype. In PAS, we suggest this is driven by fibronectin via AP-1 signalling, likely as a secondary response to myometrial scarring. Overall, this study suggests the biological processes leading to deep trophoblast invasion in the myometrium in placenta increta are as a result of upregulation of transcription factors and subsequent genes and proteins which promote trophoblast invasion. This occurs in a locally immune suppressed environment, with increased ECM degradation suggesting these findings are secondary to iatrogenic uterine injury.Significance statementPlacenta Accreta Spectrum (PAS) is a rare pregnancy complication, where the placenta fails to separate from the womb resulting in severe bleeding, which is associated with significant maternal morbidity and mortality. As Caesarean section rates increase, the incidence of PAS is increasing. The underlying pathophysiology of PAS is poorly understood. Here, we apply a spatial multi-omic approach to explore the biologic changes at the maternal-fetal interface in severe PAS (placenta increta). Using spatial transcriptomics and proteomics, we identified genes and proteins that are dysregulated in severe PAS involving processes such as extracellular matrix degradation, local immune suppression and promotion of epithelial–mesenchymal transition. This study provides new insights into the biological changes and underlying pathophysiology leading to placenta increta.

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“…The m7G modi cations are involved in gene regulation and tumor development [33]. Over-or underexpression of m7G regulators can alter m7G modi cations in tumors and affect tumor progression [34].…”

Section: Discussionmentioning

confidence: 99%

Uncovering N7-Methylguanosine regulator-mediated methylation modification pattern and Landscape of anti-PD-1/L1 Immunotherapy and immune microenvironment infiltration characterization in Lower-Grade Glioma

Maimaiti

Feng

Turhon

et al. 2022

Preprint

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Background N7-methylguanosine (m7G) modification signature has been found recently in cancer and is now known as an essential regulator of tumor progression and treatment. As a result of the function of m7G methylation modification genes in tumorigenesis and progression, there isn't much information related to the genomic profile of lower-grade gliomas (LGGs). Result In this research, bioinformatics analysis methods were used to characterize m7G modifications in individuals with LGG from The Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). Afterward, gene set enrichment analysis (GSEA), single sample GSEA (ssGSEA), CIBERSORT algorithm, ESTIMATE algorithm, R package "GSVA," and TIDE were used to evaluate the association between m7G modification patterns, TME cell infiltration properties as well as the correlation regarding immune infiltration markers. The m7G scoring scheme using principal component analysis (PCA) was employed to investigate the m7G modification patterns of individual tumors quantitatively. We examined the m7G modification hub genes' expression levels in normal samples, refractory epilepsy samples, and lower-grade glioma samples using immunohistochemistry, western-blotting, and QRT-PCR.It was discovered that individuals with LGG were categorized into two groups in terms of m7G scores (high and low) as per the properties of m7G. After observing the anti-PD-1 cohort, it has been noted that individuals having a high m7G score had significant clinical benefit, along with considerably prolonged survival duration. Opposing this, individuals in the anti-PD-L1 cohort having low m7G scores had improved prognostic outcomes and were more likely to have CR (Complete Response) / PR (Partial Response). Different m7G subtypes have different TMB (Tumor Mutational Burden) and immune profiles and might have varied responses to immunotherapy. Moreover, five potential genetic markers were found that were highly correlated with the index of the m7G score signature. Conclusion Conclusively, a thorough investigation of the features and classification associated with m7G methylation modifications may improve the clinical outcome of LGG.

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An integrated model of acinar to ductal metaplasia-related N7-methyladenosine regulators predicts prognosis and immunotherapy in pancreatic carcinoma based on digital spatial profiling

Cited by 19 publications

References 58 publications

N7-methylguanosin regulators-mediated methylation modification patterns and characterization of the immune microenvironment in lower-grade glioma

N7-methylguanosin regulators-mediated methylation modification patterns and characterization of the immune microenvironment in lower-grade glioma

Spatial proteomics and transcriptomics of placenta accreta spectrum

Uncovering N7-Methylguanosine regulator-mediated methylation modification pattern and Landscape of anti-PD-1/L1 Immunotherapy and immune microenvironment infiltration characterization in Lower-Grade Glioma

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