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Multi-Omics Analysis Identifying Key Biomarkers in Ovarian Cancer.
Ovarian cancer is one of the most common malignant tumors. Here, we aimed to study the expression and function of the CREB1 gene in ovarian cancer via the bioinformatic analyses of multiple databases. Previously, the prognosis of ovarian cancer was based on single-factor or single-gene studies. In this study, different bioinformatics tools (such as TCGA, GEPIA, UALCAN, MEXPRESS, and Metascape) have been used to assess the expression and prognostic value of the CREB1 gene. We used the Reactome and cBioPortal databases to identify and analyze CREB1 mutations, copy number changes, expression changes, and protein-protein interactions. By analyzing data on the CREB1 differential expression in ovarian cancer tissues and normal tissues from 12 studies collected from the "Human Protein Atlas" database, we found a significantly higher expression of CREB1 in normal ovarian tissues. Using this database, we collected information on the expression of 25 different CREB-related proteins, including TP53, AKT1, and AKT3. The enrichment of these factors depended on tumor metabolism, invasion, proliferation, and survival. Individualized tumors based on gene therapy related to prognosis have become a new possibility. In summary, we established a new type of prognostic gene profile for ovarian cancer using the tools of bioinformatics.
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Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19.
The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 and donor lung tissue with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage. We identify changes in cellular composition across progressive damage, including waves of molecularly distinct macrophages and depletion of epithelial and endothelial populations. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early damage, and fibrosis-related collagens in late damage. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early steps of alveolar damage. These results provide a comprehensive, spatially resolved atlas of alveolar damage progression in COVID-19, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways in severe disease.
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Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson's disease.
BACKGROUND: Glioblastoma multiforme (GBM) is the most common cancer of the central nervous system, while Parkinson's disease (PD) is a degenerative neurological condition frequently affecting the elderly. Neurotrophic factors are key factors associated with the progression of degenerative neuropathies and gliomas. METHODS: The 2601 neurotrophic factor-related genes (NFRGs) available in the Genecards portal were analyzed and 12 NFRGs with potential roles in the pathogenesis of Parkinson's disease and the prognosis of GBM were identified. LASSO regression and random forest algorithms were then used to screen the key NFRGs. The correlation of the key NFRGs with immune pathways was verified using GSEA (Gene Set Enrichment Analysis). A prognostic risk scoring system was constructed using LASSO (Least absolute shrinkage and selection operator) and multivariate Cox risk regression based on the expression of the 12 NFRGs in the GBM cohort from The Cancer Genome Atlas (TCGA) database. We also investigated differences in clinical characteristics, mutational landscape, immune cell infiltration, and predicted efficacy of immunotherapy between risk groups. Finally, the accuracy of the model genes was validated using multi-omics mutation analysis, single-cell sequencing, QT-PCR, and HPA. RESULTS: We found that 4 NFRGs were more reliable for the diagnosis of Parkinson's disease through the use of machine learning techniques. These results were validated using two external cohorts. We also identified 7 NFRGs that were highly associated with the prognosis and diagnosis of GBM. Patients in the low-risk group had a greater overall survival (OS) than those in the high-risk group. The nomogram generated based on clinical characteristics and risk scores showed strong prognostic prediction ability. The NFRG signature was an independent prognostic predictor for GBM. The low-risk group was more likely to benefit from immunotherapy based on the degree of immune cell infiltration, expression of immune checkpoints (ICs), and predicted response to immunotherapy. In the end, 2 NFRGs (EN1 and LOXL1) were identified as crucial for the development of Parkinson's disease and the outcome of GBM. CONCLUSIONS: Our study revealed that 4 NFRGs are involved in the progression of PD. The 7-NFRGs risk score model can predict the prognosis of GBM patients and help clinicians to classify the GBM patients into high and low risk groups. EN1, and LOXL1 can be used as therapeutic targets for personalized immunotherapy for patients with PD and GBM.
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Single-cell transcriptomics reveals macrophage-neutrophil crosstalk in Haematitum-induced lung injury associated with gut dysbiosis.
BACKGROUND: Haematitum is a mineral-based traditional Chinese medicine widely used in clinical applications. Both the Chinese Materia Medica and modern research indicate that it exhibits lung toxicity and should not be administered over prolonged periods. The precise mechanism underlying this toxicity, however, remains incompletely understood. PURPOSE: This study aims to systematically elucidate the toxic mechanism of lung injury induced by Haematitum administration, emphasizing the central role of the gut-lung axis in this process. METHODS: The mouse model of lung injury induced by Haematitum was established. A combination of 16S rRNA sequencing, untargeted metabolomics, and single-cell RNA sequencing was utilized to comprehensively analyze alterations in the intestinal microbiota, lung tissue metabolism, and lung cell atlas. The pharmacological validation was conducted by administering PPARγ agonists and TNF-α inhibitors. Furthermore, the detoxification effect of its classical combination with Inula japonica Thunb. was also evaluated. RESULTS: High-dose Haematitum disrupted the intestinal barrier and induced dysbiosis. Metabolites from the gut microbiota entered the bloodstream and exerted a pathogenic effect. Correlation analysis showed that gut microbiota dysbiosis is strongly associated with the pulmonary glycerophospholipid metabolic pathway. Results from single-cell sequencing and macrophage/TNF-α colocalization experiments indicated that the macrophages' PPAR signaling pathway was inhibited, inactivating their anti-inflammatory function and triggering the release of inflammatory factors such as TNF-α. Acting as a key messenger, TNF-α activated the TNF signaling pathway in neutrophils, driving them to acquire a highly destructive phenotype. The synergy between macrophages and neutrophils ultimately provoked inflammation and cell apoptosis in lung tissue. Pharmacological intervention of the PPARγ/TNF-α axis can effectively reverse cellular abnormalities and significantly alleviate lung injury. The combination with Inula japonica Thunb. also reduced lung toxicity, and components within this herb are predicted to act as natural PPARγ agonists. CONCLUSIONS: This study has revealed a potential toxic mechanism. The intestinal barrier in mice was compromised, with an increase in the relative abundance of Klebsiella, entry of microbial metabolites into the bloodstream, and disruption of glycerophospholipid metabolism in the lungs, which in turn resulted in dysfunction of pulmonary immune cells. It clarifies that the core mechanism of Haematitum-induced lung injury lies in inhibiting the PPAR signaling pathway in macrophages and activating the TNF signaling pathway in neutrophils. Administering Haematitum at a common dose or in combination with Inula japonica Thunb. mitigates these safety risks. These findings advance understanding of the toxicology of mineral-based medicines and provide a reference for the safe clinical application of these traditional Chinese medicines.
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USP15 mutation associated with autism spectrum disorder alters progenitor fate and neuronal maturation in human brain organoids.
De novo variants in the ubiquitin-proteasome pathway are linked to autism spectrum disorder (ASD), yet their functional impact on neurodevelopment remains poorly understood. We investigated USP15, a deubiquitinating enzyme with rare damaging variants identified in individuals with ASD, using isogenic human iPSC-derived brain organoids and single-cell transcriptomics. USP15 mutant organoids showed genotype-dependent, progenitor-centered alterations during corticogenesis. Heterozygous organoids modeling haploinsufficiency displayed a shift toward later pseudotime states together with altered maturation and synaptic organization of deep-layer neurons. In contrast, homozygous organoids showed broader phenotypes, including mitotic suppression, aberrant HOX gene expression, and stress-response activation. Regulon analysis showed reduced activity of progenitor-associated regulons, including SOX2, NR2F1, and NR2F2, in heterozygous organoids, whereas homozygous organoids exhibited broader changes in transcriptional regulatory networks. Furthermore, USP15 mutant-associated gene expression patterns were significantly enriched for established ASD risk genes. Comparison with the mouse brain perturbation atlas showed that the transcriptional signature of the USP15 mutant showed notable overlap with those of Fezf2 and Foxp1 mutants, key regulators of deep-layer projection neuron identity. These findings characterize genotype-dependent neurodevelopmental phenotypes associated with reduced USP15 dosage and provide a human neural framework for investigating ASD-relevant developmental mechanisms in the context of a rare ubiquitin-pathway variant.
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A low level of tumor necrosis factor α in tumor microenvironment maintains the self-renewal of glioma stem cells by Vasorin-mediated glycolysis.
BACKGROUND: Self-renewal of glioma stem cells (GSCs) is responsible for glioblastoma (GBM) therapy resistance and recurrence. Tumor necrosis factor α (TNFα) and TNF signaling pathway display an antitumor activity in preclinical models and in tumor patients. However, TNFα exhibits no significance for glioma clinical prognosis based on the Glioma Genome Atlas database. This study aimed to explore whether TNFα of tumor microenvironment maintains self-renewal of GSCs and promotes worse prognosis in glioma patients. METHODS: Spatial transcriptomics, immunoblotting, sphere formation assay, extreme limiting dilution, and gene expression analysis were used to determine the role of TNFα on GSC's self-renewal. Mass spectrometry, RNA-sequencing detection, bioinformatic analyses, qRT-RNA, immunofluorescence, immunohistochemistry, single-cell RNA sequencing, in vitro and in vivo models were used to uncover the mechanism of TNFα-induced GSC self-renewal. RESULTS: A low level of TNFα displays a promoting effect on GSC self-renewal and worse glioma prognosis. Mechanistically, Vasorin (VASN) mediated TNFα-induced self-renewal by potentiating glycolysis. Lactate produced by glycolysis inhibits the TNFα secretion of tumor-associated macrophages (TAMs) and maintains TNFα at a low level. CONCLUSIONS: TNFα-induced GSC self-renewal mediated by VASN provides a possible explanation for the failures of endogenous TNFα effect on GBM. A combination of targeting VASN and TNFα antitumor effect may be an effective approach for treating GBM.
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A computational pipeline for identifying gene targets and signalling pathways in cancer cells to improve lymphocyte infiltration and immune checkpoint therapy efficacy.
BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are crucial for effective immune checkpoint blockade (ICB) therapy in solid tumours. However, ∼70% of these tumours exhibit poor lymphocyte infiltration, rendering ICB therapies less effective. METHODS: We developed a bioinformatics pipeline integrating multiple previously unconsidered factors or datasets, including tumour cell immune-related pathways, copy number variation (CNV), and single tumour cell sequencing data, as well as tumour mRNA-seq data and patient survival data, to identify targets that can potentially improve T cell infiltration and enhance ICB efficacy. Furthermore, we conducted wet-lab experiments and successfully validated one of the top-identified genes. FINDINGS: We applied this pipeline in solid tumours of the Cancer Genome Atlas (TCGA) and identified a set of genes in 18 cancer types that might potentially improve lymphocyte infiltration and ICB efficacy, providing a valuable drug target resource to be further explored. Importantly, we experimentally validated SUN1, which had not been linked to T cell infiltration and ICB therapy previously, but was one of the top-identified gene targets among 3 cancer types based on the pipeline, in a mouse colon cancer syngeneic model. We showed that Sun1 KO could significantly enhance antigen presentation, increase T-cell infiltration, and improve anti-PD1 treatment efficacy. Moreover, with a single-cell multiome analysis, we identified subgene regulatory networks (sub-GRNs) showing Stat proteins play important roles in enhancing the immune-related pathways in Sun1-KO cancer cells. INTERPRETATION: This study not only established a computational pipeline for discovering new gene targets and signalling pathways in cancer cells that block T-cell infiltration, but also provided a gene target pool for further exploration in improving lymphocyte infiltration and ICB efficacy in solid tumours. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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A secondary role for hypoxia and HIF1 in the regulation of (IFNγ-induced) PD-L1 expression in melanoma.
Cancer cells are able to escape immune surveillance by upregulating programmed death ligand 1 (PD-L1). A key regulator of PD-L1 expression is transcriptional stimulation by the IFNγ/JAK/STAT pathway. Recent studies suggest that hypoxia can induce PD-L1 expression. As hypoxia presents a hallmark of solid tumor development, hypoxic control of PD-L1 expression may affect the efficacy of cancer immunotherapy. This study aims to explore the hypoxic regulation of PD-L1 expression in human melanoma, and its interaction with IFNγ-induced PD-L1 expression. Analysis of the cutaneous melanoma dataset from the cancer genome atlas revealed a significant correlation of the HIF1-signaling geneset signature with PD-L1 mRNA expression. However, this correlation is less pronounced than other key pathways known to control PD-L1 expression, including the IFNγ/JAK/STAT pathway. This secondary role of HIF1 in PD-L1 regulation was confirmed by analyzing single-cell RNA-sequencing data of 33 human melanoma tissues. Interestingly, PD-L1 expression in these melanoma tissues was primarily found in macrophages. However, also in these cells STAT1, and not HIF1, displayed the most pronounced correlation with PD-L1 expression. Moreover, we observed that hypoxia differentially affects PD-L1 expression in human melanoma cell lines. Knockdown of HIF1 expression indicated a minor role for HIF1 in regulating PD-L1 expression. A more pronounced influence of hypoxia was found on IFNγ-induced PD-L1 mRNA expression, which is controlled at a 952 bp PD-L1 promoter fragment. These findings, showing the influence of hypoxia on IFNγ-induced PD-L1 expression, are relevant for immunotherapy, as both IFNγ and hypoxia are frequently present in the tumor microenvironment.
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Clinical Significance and Potential Molecular Mechanisms of Angiotensin-Converting Enzyme 2 in Colorectal Cancer.
BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) exhibits tumor-suppressive potential in cancers, but its role in colorectal cancer (CRC) is unclear. The aim of the study was to investigate ACE2 expression, clinical significance, and immune microenvironment associations in CRC. METHODS: A multidimensional approach was taken using single-cell RNA sequencing and spatial transcriptomics to analyze ACE2 expression in CRC cells. High-throughput data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) (2,275 CRC and 1,269 adjacent tissues) were used to assess mRNA levels. Immunohistochemistry was performed to examine ACE2 protein expression in 66 CRC and 75 adjacent tissues. Molecular testing assessed associations with Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations. Immune infiltration was analyzed using single-sample gene set enrichment analysis (ssGSEA), focusing on 24 immune cell types, CD8+ T cells, and programmed death ligand 1 (PD-L1) correlations. RESULTS: ACE2 was highly expressed in malignant cells and Ki-67-activated regions. mRNA and protein levels were upregulated in CRC (standardized mean difference (SMD) = 0.321, area under the curve (AUC) = 0.844). High ACE2 exhibited significant associations with nerve invasion, lower expression in mucinous adenocarcinomas, and NRAS (Q61R/L/H/K) mutations. ACE2 negatively showed an inverse correlation with CD8+ T-cell infiltration (r = -0.186, P < 0.001) and PD-L1 expression (r = -0.282, P = 0.022). CONCLUSIONS: The upregulation of ACE2 is associated with nerve invasion, pathological type, and an immunosuppressive microenvironment with reduced CD8+ T-cell infiltration and PD-L1 expression.
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Association of microtubule-based processes gene expression with immune microenvironment and its predictive value for drug response in oestrogen receptor-positive breast cancer.
OBJECTIVE: The development of acquired endocrine resistance and reduced chemosensitivity in oestrogen receptor-positive (ER+) breast cancer presents significant challenges. Microtubule-based process-related genes (MBPRGs) play essential biological roles in the cell cycle and the development of migration. This study aimed to establish a novel prognostic signature based on MBPRGs to improve patient outcomes and offer additional treatment options for those with ER+ breast cancer. METHODS: Clinical data along with relevant RNA information with ER+ breast cancer were sourced from The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium. Consensus clustering was subsequently utilised to identify new molecular subgroups. Evaluations of the tumour immune microenvironment and immune status of these subgroups were performed via ESTIMATE, CIBERSORT, MCP, and ssGSEA. Additionally, functional analyses were conducted to investigate the underlying mechanisms involved. Prognostic risk models were developed via random forest, support vector machines and the least absolute shrinkage and selection operator algorithm. Single-cell analysis revealed differences in the expression levels of key genes among various cell types. Western blotting was used to measure protein levels in breast cancer cell lines. Immunohistochemical staining was used to assess protein expression in paraffin-embedded tissues, and Kaplan-Meier survival curves were generated to evaluate survival differences between the high- and low-expression groups of key genes. Transwell and cell viability assays were used to examine the biological functions of CHORDC1. RESULTS: Two molecular subgroups with significantly different survival outcomes were identified. Longer survival was linked to a high immune score, low tumour purity, a greater presence of immune infiltrating cells, and an overall positive immune status. Risk models derived from MBPRGs exhibited strong potential for predicting survival in patients with ER+ breast cancer. Key genes had elevated protein levels in differentiated breast cancer cell lines, and elevated CHORDC1 expression was linked to a tendency towards a worse outcome in patients with ER+ breast cancer. Silencing CHORDC1 inhibited cell viability and invasion, reducing sensitivity to tamoxifen and paclitaxel in vitro. CONCLUSION: MBPRG expression is linked to the immune microenvironment and drug resistance in ER+ breast cancer patients, providing a reliable prognostic indicator for this group.