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High-resolution transcriptome atlas of bladder cancer highlights the functional myeloid subsets in modulating immune microenvironment.
BACKGROUND: Despite the recent advancements in characterizing the heterogeneity of the tumour microenvironment (TME), the immunological understanding of myeloid subsets in bladder cancer (BC) remains restricted. A more comprehensive exploration of myeloid cells in BC may uncover critical immune-modulating features. METHODS: We employed density gradient centrifugation to enrich the population of immune cells and collected paired tumour and normal bladder tissues from 11 patients with bladder cancer for single-cell transcriptome analysis. Additionally, in vitro cultures and mouse tumour models were further used to validate our findings. FINDINGS: We revealed the metabolic alterations in TREM2+ macrophages and CMA1+ mast cells within BC tissues, and further demonstrated that knockout of Trem2 significantly reprogrammed the TME and upregulated PD-L1 expression on dendritic cells (DCs). Our deconvolution analysis elucidated the prognostic value of CMA1+ mast cells, CD1C+ DCs and LAMP3+ DCs in BC, as well as delineated four distinct immune cellular modules to investigate their cellular associations. Furthermore, our exploration of the interactome landscapes highlighted the anti-tumour effect of App knockdown in remodelling the TME, as well as the pivotal roles of ANNEXIN and GALECTIN pathways in BC pathogenesis. INTERPRETATION: Our findings provide a high-resolution resource for BC, elucidating the functional myeloid cell states, including TREM2+ macrophages, CMA1+ mast cells, and CD1C+ DCs. Furthermore, our study demonstrates that TREM2 and APP function as immune-modulating molecules, with potential therapeutic implications in the context of bladder cancer. FUNDING: National Natural Science Foundation of China (31991174); the National Key Research and Development Program of China (2021YFA1301603 and 2023YFC2507000); the National Basic Science Center Program of China (82388101); the National Key Research and Development Program of China (2019YFA0508502 and 2022YFC2505001).
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High expression of SIGLEC7 may promote M2-type macrophage polarization leading to adverse prognosis in glioma patients.
INTRODUCTION: Gliomas are the most common primary intracranial tumors, known for their high invasiveness and destructiveness. Sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC7) is present in various immune cells, especially macrophages, and significantly affects immune homeostasis and cancer cell response. However, research on the role and prognostic impact of SIGLEC7 in glioma patients is currently limited. METHODS: We utilized transcriptomic data from 702 glioma patients in The Cancer Genome Atlas (TCGA) and 693 glioma patients in the Chinese Glioma Genome Atlas (CGGA), along with clinical samples we collected, to comprehensively investigate the impact of SIGLEC7 on glioma expression patterns, biological functions, and prognostic value. We focused on its role in glioma-related immune responses and immune cell infiltration and analyzed its expression at the single-cell level. Finally, we validated the role of SIGLEC7 in gliomas through tissue and cell experiments. RESULTS: SIGLEC7 expression was significantly increased in glioma patients with malignant characteristics. Survival analysis indicated that glioma patients with high SIGLEC7 expression had significantly lower survival rates. Gene function analysis revealed that SIGLEC7 is primarily involved in immune and inflammatory responses and is strongly negatively correlated with tumor-associated immune regulation. Additionally, the expression of most immune checkpoints was positively correlated with SIGLEC7, and immune cell infiltration analysis clearly demonstrated a significant positive correlation between SIGLEC7 expression and M2 macrophage infiltration levels. Single-cell analysis, along with tissue and cell experiments, confirmed that SIGLEC7 enhances macrophage polarization towards the M2 phenotype, thereby promoting glioma invasiveness through the immunosuppressive effects of M2 macrophages. Cox regression analysis and the establishment of survival prediction models indicated that high SIGLEC7 expression is an unfavorable prognostic factor for glioma patients. DISCUSSION: High SIGLEC7 expression predicts poor prognosis in glioma patients and is closely associated with M2 macrophages in the tumor environment. In the future, SIGLEC7 may become a promising target for glioma immunotherapy.
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MAX deficiency impairs human endometrial decidualization through down-regulating OSR2 in women with recurrent spontaneous abortion.
Human uterine stromal cell undergoes decidualization for pregnancy establishment and maintenance, which involved extensive proliferation and differentiation. Increasing studies have suggested that recurrent spontaneous abortion (RSA) may result from defective endometrial stromal decidualization. However, the critical molecular mechanisms underlying impaired decidualization during RSA are still elusive. By using our recently published single-cell RNA sequencing (scRNA-seq) atlas, we found that MYC-associated factor X (MAX) was significantly downregulated in the stromal cells derived from decidual tissues of women with RSA, followed by verification with immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). MAX knockdown significantly impairs human endometrial stromal cells (HESCs) proliferation as determined by MTS assay and Ki67 immunostaining, and decidualization determined by F-actin, and decidualization markers. RNA-seq together with chromatin immunoprecipitation sequencing (ChIP-seq) and cleavage under targets and release using nuclease sequencing (CUT&RUN-seq) analysis were applied to explore the molecular mechanisms of MAX in regulation of decidualization, followed by dual-luciferase reporter assay to verify that MAX targets to (odd-skipped related transcription factor 2) OSR2 directly. Reduced expression of OSR2 was also confirmed in decidual tissues in women with RSA by IHC and qRT-PCR. OSR2 knockdown also significantly impairs HESCs decidualization. OSR2-overexpression could at least partly rescue the downregulated insulin-like growth factor binding protein 1 (IGFBP1) expression level in response to MAX knockdown. Collectively, MAX deficiency observed in RSA stromal cells not only attenuates HESCs proliferation but also impairs HESCs decidualization by downregulating OSR2 expression at transcriptional level directly.
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The Comprehensive Analysis of Weighted Gene Co-Expression Network Analysis and Machine Learning Revealed Diagnostic Biomarkers for Breast Implant Illness Complicated with Breast Cancer.
PURPOSE: An increasing number of breast cancer (BC) patients choose prosthesis implantation after mastectomy, and the occurrence of breast implant illness (BII) has received increasing attention and the underlying molecular mechanisms have not been clearly elucidated. This study aimed to identify the crosstalk genes between BII and BC and explored their clinical value and molecular mechanism initially. METHODS: We retrieved the data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), and identified the differentially expressed genes (DEG) as well as module genes using Limma and weighted gene co-expression network analysis (WGCNA). Enrichment analysis, the protein-protein interaction network (PPI), and machine learning algorithms were performed to explore the hub genes. We employed a nomogram and receiver operating characteristic curve to evaluate the diagnostic accuracy. Single-cell analysis disclosed variations in the expression of key genes across distinct cellular populations. The expression levels of the key genes were further confirmed in BC cell lines. Immunohistochemical analysis was utilized to examine protein levels from 25 patients with breast cancer undergoing prosthetic implant surgery. Ultimately, we deployed single-sample Gene Set Enrichment Analysis (ssGSEA) to scrutinize the immunological profiles between the normal and BC cohorts, as well as between the non-BII and BII groups. RESULTS: WGCNA identified 1137 common genes, whereas DEG analysis found 541 overlapping genes in BII and BC. After constructing the PPI network, 17 key genes were selected, and three potential hub genes include KRT14, KIT, ALB were chosen for nomogram creation and diagnostic assessment through machine learning. The validation of these results was conducted by examining gene expression patterns in the validation dataset, breast cancer cell lines, and BII-BC patients. However, ssGSEA uncovered different immune cell infiltration patterns in BII and BC. CONCLUSION: We pinpointed shared three central genes include KRT14, KIT, ALB and molecular pathways common to BII and BC. Shedding light on the complex mechanisms underlying these conditions and suggesting potential targets for diagnostic and therapeutic strategies.
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SnRNA-seq reveals the ameliorative effects of optimized Xueyu Jingshen formula on high altitude cerebral edema by modulating energy metabolism, inflammation and BBB integrity.
BACKGROUND: High-altitude cerebral edema (HACE) is a type of lethal neurological emergency, whose underlying pathogenic mechanisms and core therapeutic targets remain largely unelucidated to date. Optimized Xueyu Jingshen formula (OXJF) has been shown to exert definite clinical efficacy in the intervention of HACE, whereas the underlying molecular mechanisms remain to be systematically and deeply explored. PURPOSE: This work leverages single-nucleus RNA sequencing (snRNA-seq) to elucidate pathological rewiring of cell-type-specific interactions in HACE, and to uncover molecular targets of OXJF, thereby laying the groundwork for novel clinical therapeutic strategies. METHODS: We firstly conducted a qualitative analysis of the chemical components of OXJF using UHLPC-Q-TOF-MS. We comprehensively evaluated the pharmacodynamic effects of OXJF firstly by detecting the behavioral changes, brain water content, BBB permeability and pathological damage of HACE mice, combined with the analysis of cerebral microvascular blood flow imaging. Afterwards, we constructed a cerebral cell atlas of HACE mice by using snRNA-seq and achieved systematic identification of various cell types. The proportion of each cell type was quantified and verified through multiplex immunofluorescence. AUCell was employed to ascertain the activity of gene modules, thereby identifying cell population exhibiting specific functional states or transcriptional signatures. Differential genes and signaling pathways enrichment analyses were employed to elucidate vital biomarkers and pathways. To clarify the differentiation patterns of cell subtypes, we introduced pseudotime analysis for relevant investigations. CellChat was performed to decipher cell-cell communication networks based on ligand-receptor pairs analysis. Ultimately, we verified whether mitochondrial Complex I was the pivotal target mediating cellular responses to hypoxic stimulation and OXJF intervention in C8-D1A, HT22, BV2 and MO3.13 cell lines. RESULTS: A total of 163 chemical components, mainly including flavonoids, organic acids and terpenoids, were successfully identified. Pharmacodynamic experiments certified that OXJF could largely improve cognitive and motor functions, and reduce BWC in HACE mice. Meanwhile, by upregulating the expression of tight junction proteins, OXJF reversed high-altitude-induced increases in BBB permeability, and effectively alleviated cerebral microvascular hemodynamic disorders as well as pathological damage in HACE mice. 92,616 annotated nuclei were mainly identified as astrocyte, excitatory and inhibitory neurons, microglia, oligodendrocyte precursor cells and oligodendrocytes. Cell proportion analysis and multiplex immunofluorescence staining verified that no significant alterations in the proportions of the aforementioned cell populations were observed in both HACE mice and OXJF-treated mice. Gene modules associated with energy metabolism, inflammation and BBB integrity exhibited high AUCell scores, implying their potential involvement as underlying mechanisms through which OXJF ameliorated HACE. Furthermore, key regulatory components within the above modules were identified including Hif1a, Vhl, Ikbkb, Rela, Tlr4, Tnfrsf11a, Irak1, Ndufb8, Nfe2l2, Ndufs4, Vegfa, Pdgfa and Gja1 genes. Cell trajectory analysis indicated that diverse cell types manifested marked heterogeneity in response to HACE and OXJF intervention. Further CellChat analysis unveiled widespread ligand-receptor interactions across cell population, and these interactions were mapped to central signaling molecules including ADGRB, EPHB, PTN, UNC5, CLDN, CypA, JAM, SLIT and GAP. In vitro cellular assays had confirmed that OXJF suppressed reactive oxygen species production and mitochondrial permeability transition pore opening via upregulating the expression of mitochondrial Complex Ⅰ subunits NDUFA9, NDUFS4 and NDUFB8. This effect drove a noteworthy increase in ATP content, which in turn rescued energy supply in C8-D1A, HT22, BV2 and MO3.13 cell lines. CONCLUSION: This study provides and defines the first systematic snRNA-seq profiles under OXJF-treated HACE mice. The potential mechanisms of OXJF in treating HACE were related to maintaining energy metabolism, inflammation and BBB homeostasis.
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Extracellular cancer‑associated fibroblasts: A novel subgroup in the cervical cancer microenvironment that exhibits tumor‑promoting roles and prognosis biomarker functions.
Tumor invasion and metastasis are the processes that primarily cause adverse outcomes in patients with cervical cancer. Cancer-associated fibroblasts (CAFs), which participate in cancer progression and metastasis, are novel targets for the treatment of tumors. The present study aimed to assess the heterogeneity of CAFs in the cervical cancer microenvironment through single-cell RNA sequencing. After collecting five cervical cancer samples and obtaining the CAF-associated gene sets, the CAFs in the cervical cancer microenvironment were divided into myofibroblastic CAFs and extracellular (ec)CAFs. The ecCAFs appeared with more robust pro-tumorigenic effects than myCAFs according to enrichment analysis. Subsequently, through combining the ecCAF hub genes and bulk gene expression data for cervical cancer obtained from The Cancer Genome Atlas and Gene Ontology databases, univariate Cox regression and least absolute shrinkage and selection operator analyses were performed to establish a CAF-associated risk signature for patients with cancer. The established risk signature demonstrated a stable and strong prognostic capability in both the training and validation cohorts. Subsequently, the association between the risk signature and clinical data was evaluated, and a nomogram to facilitate clinical application was established. The risk score was demonstrated to be associated with both the tumor immune microenvironment and the therapeutic responses. Moreover, the signature also has predictive value for the prognosis of head and neck squamous cell carcinoma, and bladder urothelial carcinoma, which were also associated with human papillomavirus infection. In conclusion, the present study assessed the heterogeneity of CAFs in the cervical cancer microenvironment, and a subgroup of CAFs that may be closely associated with tumor progression was defined. Moreover, a signature based on the hub genes of ecCAFs was shown to have biomarker functionality in terms of predicting survival rates, and therefore this CAF subgroup may become a therapeutic target for cervical cancer in the future.
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Decoding the epithelial-stromal interactome in allergic rhinitis through single-cell multiomics integration.
BACKGROUND: Allergic rhinitis (AR) is a prevalent chronic condition, yet the cellular and molecular changes associated with its pathogenesis remain incompletely understood. OBJECTIVE: We sought to construct a comprehensive cellular atlas of the nasal mucosa in AR and nonallergic rhinitis and elucidate disease-associated transcriptional and epigenetic alterations. METHODS: We performed single-cell RNA sequencing and single-cell ATAC sequencing on nasal mucosa samples from 39 subjects (25 AR, 14 nonallergic rhinitis). Differentially expressed gene analysis, differentially accessible peaks analysis, cell-cell communication, trajectory inference, and gene regulatory network reconstruction were applied. A deep learning framework was developed to integrate multiomics data for disease prediction. RESULTS: We profiled 1,024,146 cells, constructing a comprehensive nasal mucosa atlas. The AR epithelium exhibited aberrant differentiation with suppressed maturation of basal and club cells, while fibroblasts displayed inflammatory activation and matrix remodeling signatures. Epithelial-stromal cross talk was enhanced in the AR group. Cell subset-specific epigenetic alterations were also observed. Single-cell multiomics for AR integrative analysis, or scMARIA, can simultaneously predict AR risk and clinically relevant disease parameters, and prioritize putative cell type-specific regulatory linkages. CONCLUSION: This multiomics study establishes a comprehensive molecular framework of the nasal mucosa, revealing dysregulated epithelial-stromal interactions and gene regulatory networks that are correlated with AR status.
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Clinical characterization of EFHD2 (swiprosin-1) in Glioma-associated macrophages and its role in regulation of immunosuppression.
Glioblastoma has been extensively studied due to its high mortality and short survival. The evolution mechanism of tumor-associated macrophages (TAMs) to Glioma-associated microglia and macrophages (GAMs) in the tumor microenvironment (TME) remains to be elucidated. The tumor cell-to-cell interaction patterns have not been well defined yet. The EF-Hand Domain Family Member D2 (EFHD2) has been reported to be differentially expressed as an immunomodulatory molecule in a variety of cancers. But large-scale clinical data from multiple ethnic communities have not been used to investigate the role of EFHD2 in glioma. RNA-seq data from 313 or 657 glioma patients from the Chinese Glioma Genome Atlas (CGGA) database and 603 glioma patients from the Cancer Genome Atlas (TCGA) database were analyzed retrospectively. Cell localization was performed using single-cell sequencing data from the CGGA database and the GSE131928 dataset. Mouse glioma cell lines and primary macrophages isolated from Efhd2 knockout mice were co-cultured to validate the immunomodulatory effects of EFHD2 on macrophages and the remodeling of TME of glioblastoma. EFHD2 is enriched in high-grade gliomas, isocitrate dehydrogenase wild-type, and 1p/19q non-co-deficient gliomas. It is a potential biomarker of glioma-proneuronal subtypes and an independent prognostic factor for overall survival in patients with malignant glioblastoma. EFHD2 regulates the monocyte-macrophage system function and positively correlates with immunosuppressive checkpoints. Further experimental data demonstrates that Efhd2 influences the polarization state of GAMs and inhibits the secretion of TGF-β1. In vitro experiments have revealed that macrophages lacking Efhd2 suppress the vitality of two glioma cell lines and decelerate the growth of glioma xenografts. In conclusion, EFHD2 promises to be a key target for TME-related immunotherapy.
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Bioinformatics analysis of aging-related genes in thoracic aortic aneurysm and dissection.
OBJECTIVE: Thoracic aortic aneurysm and dissection (TAAD) is a cardiovascular disease with a high mortality rate. Aging is an important risk factor for TAAD. This study explored the relationship between aging and TAAD and investigated the underlying mechanisms, which may contribute to the diagnosis and treatment of TAAD. METHODS: Human aging genes were obtained from the Aging Atlas official website. Various datasets were downloaded from the GEO database:the human TAAD dataset GSE52093 were used for screening differentially expressed genes (DEGs); GSE137869, GSE102397 and GSE153434 were used as validation sets, and GSE9106 was used for diagnostic prediction of receiver operating characteristic (ROC) curves. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction (PPI) network analysis were used to screen differentially co-expressed genes from human aging genes and TAAD. Using five methods of the cytoHubba plugin in Cytoscape software (Degree, Closeness, EPC, MNC, Radiality), hub genes were identified from the differentially co-expressed genes. Single-cell RNA sequencing was used to verify the expression levels of hubgenes in different cell types of aortic tissue. ROC curves were used to further screen for diagnostic genes. RESULTS: A total of 70 differentially co-expressed genes were screened from human aging genes and DEGs in human TAAD dataset GSE52093. GO enrichment analysis revealed that the DEGs played a major role in regulating DNA metabolism and damaged DNA binding. KEGG enrichment analysis revealed enrichment in the longevity regulating pathway, cellular senescence, and HIF-1 signaling pathway. GSEA indicated that the DEGs were concentrated in the cell cycle and aging-related p53 signaling pathway. The five identified hubgenes were MYC, IL6, HIF1A, ESR1, and PTGS2. Single-cell sequencing of the aging rat aorta showed that hubgenes were expressed differently in different types of cells in aortic tissue. Among these five hubgenes, HIF1A and PTGS2 were validated in the aging dataset GSE102397; MYC, HIF1A and ESR1 were validated in the TAAD dataset GSE153434. The combined area under the diagnostic ROC curve (AUC) values for the five hub genes were >0.7 in the testing and training sets of the dataset GSE9106. The combined AUC values of MYC and ESR1 were equal to the combin ed AUC values of the five hub genes. CONCLUSION: The HIF-1 signaling pathway may play an important role in TAAD and aging. MYC and ESR1 may have diagnostic value for aging-related TAAD.
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A predefined sulphur-handling transcriptional programme is associated with colorectal cancer molecular subtypes.
BACKGROUND: Colorectal cancer (CRC) exhibits substantial metabolic and transcriptomic heterogeneity, but the relationship between sulphur-handling transcriptional programmes and consensus molecular subtypes (CMS) remains incompletely resolved. METHODS: We analysed a predefined 14-gene sulphur-handling panel across The Cancer Genome Atlas colon and rectal adenocarcinoma cohorts (TCGA-COAD/READ) and six independent HG-U133 validation cohorts (n = 1,337 tumours). Analytical workflows integrated differential expression comparing tumours with adjacent-normal mucosa, CMS association modelling, random-effects meta-analysis, adjustment for three orthogonal tumour-purity estimators (ESTIMATE, consensus purity estimates, and ABSOLUTE), reference-based single-cell deconvolution with independent cross-atlas verification, and direction-aware therapeutic triage. RESULTS: Colorectal tumours demonstrated branch-specific transcriptional alterations, marked by coordinated downregulation of sulphur oxidation and clearance genes (SQOR, ETHE1, TST) and of the cysteine-catabolism genes CDO1 and CTH, and selective upregulation of SLC7A11 and AHCY, whereas CBS was not significantly altered. The composite programme score differed across CMS subtypes and was consistently lower in mesenchymal CMS4 tumours than in non-CMS4 tumours across all discovery and validation series. This association remained statistically detectable after adjustment for three global tumour-purity metrics. The programme score showed no statistically detectable independent association with overall, recurrence-free, or disease-free survival. Single-cell deconvolution supported expression across epithelial, stromal, and immune compartments. Direction-aware therapeutic triage prioritised SLC7A11/xCT inhibition as an exploratory candidate for preclinical testing. CONCLUSION: Sulphur-handling transcriptional architecture is reproducibly linked to CRC molecular taxonomy and is not fully explained by measured tumour purity variation, providing a computational framework for future functional and compartment-resolved investigation of sulphur metabolism in stratified CRC populations.