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Transcriptional landscape of pleural mesothelioma patients in relation to NF2 gene mutational status.
BACKGROUND: Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis, often driven by asbestos exposure. Mutations in the NF2 gene, a key regulator of the Hippo signaling pathway, are frequently observed in PM. However, their impact on tumor biology, immune infiltration, cytokine signaling, and therapeutic response remains poorly understood. METHODS: Using data from The Cancer Genome Atlas, we analyzed 82 PM cases to assess the prevalence and consequences of NF2 mutations. Logistic regression was used to evaluate associations with clinical variables, while transcriptomic differences were examined through differential expression and functional enrichment analyses. Immune and stromal infiltration were inferred via the xCell algorithm, cytokine signaling analyzed with Cytosig, and chemotherapeutic sensitivity predicted using the pRRophetic R package. Single-cell RNA sequencing data provided further insights into transcriptional patterns in NF2-mutated tumors. RESULTS: NF2 mutations were present in 22% of cases, with no significant correlations to histological subtype, stage, or age. NF2-mutated tumors exhibited increased infiltration of basophils, naïve B cells, and pericytes, along with altered cytokine profiles, including NRG1, TGFB3, and reduced FGF2. Differentially expressed genes, such as MYL7 and HOXA11, were linked to poorer survival. Chemotherapy modeling indicated higher sensitivity to camptothecin and vinblastine in NF2-mutated tumors. CONCLUSIONS: NF2 mutations influence the tumor microenvironment, transcriptional landscape, and predicted therapeutic response in PM, underscoring their potential as prognostic biomarkers. These findings support tailored therapeutic strategies targeting NF2-related pathways, including Hippo signaling and cytokine modulation.
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Atlas of Metastatic Gastric Cancer Links Ferroptosis to Disease Progression and Immunotherapy Response.
BACKGROUND & AIMS: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve patients with GAC poses a significant challenge, limiting the scope of current research, which has focused predominantly on localized tumors. This gap hinders deeper insight into the metastatic dynamics of GAC. METHODS: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, using cell lines and multiple patient-derived xenograft and novel mouse models of GAC. RESULTS: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of tumor microenvironment phenotypes, supporting the notion that cancer cells and their local tumor microenvironments co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 up-regulation during GAC progression. Conditional depletion of Gpx4 or pharmacologic inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. In addition, ferroptosis-resensitizing treatments augmented the efficacy of chimeric antigen receptor T-cell therapy. CONCLUSIONS: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with chimeric antigen receptor T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.
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HCG18 Participates in Vascular Invasion of Hepatocellular Carcinoma by Regulating Macrophages and Tumor Stem Cells.
OBJECTIVES: To identify key genes involved in vascular invasion in hepatocellular carcinoma (HCC), to describe their regulatory mechanisms, and to explore the immune microenvironment of HCC. METHODOLOGY: In this study, the genome, transcriptome, and immune microenvironment of HCC were assessed by using multi-platform data from The Cancer Genome Atlas (n = 373) and GEO data (GSE149614). The key regulatory networks, transcription factors and core genes related to vascular invasion and prognosis were explored based on the CE mechanism. Survival analysis and gene set enrichment were used to explore pathways related to vascular invasion. Combined with single-cell transcriptome data, the distribution of core gene expression in various cells was observed. Cellular communication analysis was used to identify key cells associated with vascular invasion. Pseudo-temporal locus analysis was used to explore the regulation of core genes in key cell phenotypes. The influence of core genes on current immune checkpoint therapy was evaluated and correlations with tumor stem cell scores were explored. RESULTS: We obtained a network containing 1,249 pairs of CE regulatory relationships, including 579 differential proteins, 28 non-coding RNAs, and 37 miRNAs. Three key transcription factors, ILF2, YBX1, and HMGA1, were identified, all regulated by HCG18 lncRNA. ScRNAseq showed that HCG18 co-localized with macrophages and stem cells. CIBERSORTx assessed 22 types of immune cells in HCC and found that HCG18 was positively correlated with M0 macrophages, while being negatively correlated with M1 and M2 macrophages, monocytes, and dendritic cells. Cluster analysis based on patient prognosis suggested that regulating phenotypic transformation of macrophages could be an effective intervention for treating HCC. At the same time, higher expression of HCG18, HMGA1, ILF2, and YBX1 was associated with a higher stem cell score and less tumor differentiation. Pan cancer analysis indicated that high expression of HCG18 implies high sensitivity to immune checkpoint therapy. CONCLUSION: HCG18 participates in vascular invasion of HCC by regulating macrophages and tumor stem cells through three key transcription factors, YBX1, ILF2, and HMGA1.
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Therapeutic Targeting of Oxidative Phosphorylation in Microsatellite Instability-High Gastric Cancer.
BACKGROUND: Gastric cancer is the third leading cause of cancer-related mortality worldwide. According to The Cancer Genome Atlas (TCGA), it can be classified into four molecular subtypes, including microsatellite instability (MSI) and genomically stable (GS) subtypes, which display distinct clinical and pathological features. However, differences in their tumor microenvironment, particularly metabolic reprogramming, remain poorly understood. METHODS: Single-cell RNA sequencing data from gastric cancer patients classified as GS or MSI were enrolled. Cell clusters were identified and annotated to compare cellular landscapes between subtypes. Differential gene expression and pathway analyses were performed among malignant epithelial cells. Key genes related to oxidative phosphorylation were identified using LASSO regression, and their expression was further validated in the TCGA dataset. Patient-derived xenograft models were used to compare tumor growth rates, ATP levels, and expression of oxidative phosphorylation -related genes. RESULTS: Single-cell transcriptomic analysis revealed eight major cell types in MSI tumors. Compared to the GS subtype, MSI samples showed significantly greater infiltration of T cells and a lower proportion of epithelial cells. Malignant cells from MSI samples exhibited increased activity of oxidative phosphorylation pathways. LASSO regression identified five oxidative phosphorylation-related genes that were consistently overexpressed in MSI tumors in both single-cell and TCGA datasets. In Patient-derived xenograft models, MSI tumors grew more rapidly and demonstrated higher ATP levels and elevated expression of the five oxidative phosphorylation-related genes compared to MSS tumors. CONCLUSION: Our study reveals enhanced oxidative phosphorylation metabolism in MSI gastric cancer at single-cell resolution and identifies five oxidative phosphorylation-related genes that may serve as potential therapeutic targets for this subtype.
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Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators.
Alternative splicing (AS) dramatically expands the complexity of the mammalian brain transcriptome, but its atlas remains incomplete. Here we performed deep mRNA sequencing of mouse cortex to discover and characterize alternative exons with potential functional significance. Our analysis expands the list of AS events over 10-fold compared with previous annotations, demonstrating that 72% of multiexon genes express multiple splice variants in this single tissue. To evaluate functionality of the newly discovered AS events, we conducted comprehensive analyses on central nervous system (CNS) cell type-specific splicing, targets of tissue- or cell type-specific RNA binding proteins (RBPs), evolutionary selection pressure, and coupling of AS with nonsense-mediated decay (AS-NMD). We show that newly discovered events account for 23-42% of all cassette exons under tissue- or cell type-specific regulation. Furthermore, over 7,000 cassette exons are under evolutionary selection for regulated AS in mammals, 70% of which are new. Among these are 3,058 highly conserved cassette exons, including 1,014 NMD exons that may function directly to control gene expression levels. These NMD exons are particularly enriched in RBPs including splicing factors and interestingly also regulators for other steps of RNA metabolism. Unexpectedly, a second group of NMD exons reside in genes encoding chromatin regulators. Although the conservation of NMD exons in RBPs frequently extends into lower vertebrates, NMD exons in chromatin regulators are introduced later into the mammalian lineage, implying the emergence of a novel mechanism coupling AS and epigenetics. Our results highlight previously uncharacterized complexity and evolution in the mammalian brain transcriptome.
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Magnesium sulfate attenuates sepsis-induced myocardial injury through macrophage Fxyd2/NF-κB signaling: Integrated evidence from a propensity-matched cohort, single-cell atlas, and mechanistic validation.
BACKGROUND: Sepsis-induced myocardial injury (SIMI) affects approximately 20%-55% of septic patients, with associated mortality ranging from 37% to 70%; however, evidence for magnesium sulfate (MgSO₄) as a targeted SIMI intervention and its molecular basis remain poorly defined. METHODS: We integrated three evidentiary levels. A retrospective cohort of 2219 SIMI patients from the MIMIC-IV database underwent 1:1 propensity score matching (PSM; n = 992) and piecewise Cox regression (Day 10 landmark) to evaluate 28-day mortality. Single-cell RNA sequencing (scRNA-seq) of murine septic cardiac tissue characterized immune dynamics and identified MgSO₄-responsive targets. A macrophage-cardiomyocyte conditioned-medium transfer model, supplemented by Western blotting, RT-qPCR, and pyroptosis assays, validated the Fxyd2/NF-κB axis. RESULTS: MgSO₄ conferred robust survival benefit during the acute phase (Days 0-10; aHR = 0.402, 95% CI: 0.302-0.536, P < 0.001), representing a 59.8% relative risk reduction. The benefit was independent of baseline serum magnesium, indicating a pharmacological rather than nutritional effect. scRNA-seq revealed MgSO₄ enriched reparative macrophage subsets via mineral absorption pathways, identifying Fxyd2 as a key responsive gene. In vitro, MgSO₄ pretreatment remodeled the macrophage secretome-suppressing TNF-α, IL-6, and MCP-1-thereby abrogating paracrine NLRP3-caspase-1-GSDMD pyroptosis in H9c2 cardiomyocytes. Mechanistically, MgSO₄ preserved Fxyd2 expression in LPS-stimulated macrophages, inhibiting NF-κB phosphorylation and downstream pro-inflammatory transcription. CONCLUSIONS: MgSO₄ provides time-dependent cardioprotection in SIMI by reprogramming the macrophage secretome via the Fxyd2/NF-κB axis, repositioning it as a targeted immunomodulatory agent and providing rationale for early administration in future randomized trials.
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scProAtlas: an atlas of multiplexed single-cell spatial proteomics imaging in human tissues.
Spatial proteomics can visualize and quantify protein expression profiles within tissues at single-cell resolution. Although spatial proteomics can only detect a limited number of proteins compared to spatial transcriptomics, it provides comprehensive spatial information with single-cell resolution. By studying the spatial distribution of cells, we can clearly obtain the spatial context within tissues at multiple scales. Spatial context includes the spatial composition of cell types, the distribution of functional structures, and the spatial communication between functional regions, all of which are crucial for the patterns of cellular distribution. Here, we constructed a comprehensive spatial proteomics functional annotation knowledgebase, scProAtlas (https://relab.xidian.edu.cn/scProAtlas/#/), which is designed to help users comprehensively understand the spatial context within different tissue types at single-cell resolution and across multiple scales. scProAtlas contains multiple modules, including neighborhood analysis, proximity analysis and neighborhood network, to comprehensively construct spatial cell maps of tissues and multi-modal integration, spatial gene identification, cell-cell interaction and spatial pathway analysis to display spatial variable genes. scProAtlas includes data from eight spatial protein imaging techniques across 15 tissues and provides detailed functional annotation information for 17 468 394 cells from 945 region of interests. The aim of scProAtlas is to offer a new insight into the spatial structure of various tissues and provides detailed spatial functional annotation.
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Identification of Ligand-Receptor Pairs Associated With Tumour Characteristics in Clear Cell Renal Cell Carcinoma.
The tumour microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) comprises multiple cell types, which promote tumour progression and modulate drug resistance and immune cell infiltrations via ligand-receptor (LR) interactions. However, the interactions, expression patterns, and clinical relevance of LR in the TME in ccRCC are insufficiently characterised. This study characterises the complex composition of the TME in ccRCC by analysing the single-cell sequencing (scRNA-seq) data of patients with ccRCC from the Gene expression omnibus database. On analysing the scRNA-seq data combined with the cancer genome atlas kidney renal clear cell carcinoma (TCGA-KIRC) dataset, 46 LR-pairs were identified that were significantly correlated and had prognostic values. Furthermore, a new molecular subtyping model was proposed based on these 46 LR-pairs. Molecular subtyping was performed in two ccRCC cohorts, revealing significant differences in prognosis between the subtypes of the two ccRCC cohorts. Different molecular subtypes exhibited different clinicopathological features, mutational, pathway, and immune signatures. Finally, the LR.score model that was constructed using ten essential LR-pairs that were identified based on LASSO Cox regression analysis revealed that the model could accurately predict the prognosis of patients with ccRCC. In addition, the differential expression of ten LR-pairs in tumour and normal cell lines was identified. Further functional experiments showed that CX3CL1 can exert anti-tumorigenic role in ccRCC cell line. Altogether, the effects of immunotherapy were connected to LR.scores, indicating that potential medications targeting these LR-pairs could contribute to the clinical benefit of immunotherapy. Therefore, this study identifies LR-pairs that could be effective biomarkers and predictors for molecular subtyping and immunotherapy effects in ccRCC. Targeting LR-pairs provides a new direction for immunotherapy regimens and prognostic evaluations in ccRCC.
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Profiling human breast epithelial cells using single cell RNA sequencing identifies cell diversity.
Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis. Several distinct epithelial subpopulations have been proposed, but complete understanding of the spectrum of heterogeneity and differentiation hierarchy in the human breast remains elusive. Here, we use single-cell mRNA sequencing (scRNAseq) to profile the transcriptomes of 25,790 primary human breast epithelial cells isolated from reduction mammoplasties of seven individuals. Unbiased clustering analysis reveals the existence of three distinct epithelial cell populations, one basal and two luminal cell types, which we identify as secretory L1- and hormone-responsive L2-type cells. Pseudotemporal reconstruction of differentiation trajectories produces one continuous lineage hierarchy that closely connects the basal lineage to the two differentiated luminal branches. Our comprehensive cell atlas provides insights into the cellular blueprint of the human breast epithelium and will form the foundation to understand how the system goes awry during breast cancer.
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Arecoline Is Associated With Inhibition of Cuproptosis and Proliferation of Cancer-Associated Fibroblasts in Oral Squamous Cell Carcinoma: A Potential Mechanism for Tumor Metastasis.
BACKGROUND: Metastatic disease remains the primary cause of death in patients with oral squamous cell carcinoma (OSCC), especially those who use betel nut. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are regarded as a significant component in the TME of OSCC. However, the precise mechanisms regulating CAFs in OSCC are poorly understood. METHODS: Thirteen genes related to the arecoline were analyzed to explore the significant ones involved in arecoline-related OSCC metastasis. The GSE139869 (n = 10) and The Cancer Genome Atlas (TCGA)-OSCC data (n = 361) were mined for the identification of the differentially expressed genes. The least absolute shrinkage and selection operator (LASSO) regression was performed to identify the independent prognostic signatures. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore the functional enrichment of selected genes, and gene set enrichment analysis of cuproptosis-related genes was completed. Spearman's analysis and Tumor Immune Estimation Resource (TIMER) were used to visualize the correlation between the infiltration of CAFs and the gene expression. The correlation analysis of the cells and different genes, including CAF infiltration and transcripts per million expression, was assessed. The relationship between arecoline and CAFs was confirmed by cell counting kit-8 assay (CCK-8). CancerSEA was searched to identify the single-cell phenotype. RESULT: Arecoline-associated fibrosis-related OSCC differentially expressed genes (AFOC-DEGs), namely, PLAU, IL1A, SPP1, CCL11, TERT, and COL1A2, were screened out and selected from the Gene Expression Omnibus (GEO) database and TCGA database. AFOC-DEGs were highly expressed in OSCC, which led to poor survival of patients. Functional enrichment analysis, protein-protein interaction network construction, and Spearman's correlation analysis all suggested that AFOC-DEGs were closely associated with cuproptosis. Cellular experiments demonstrated that arecoline stimulation could significantly increase the cell viability of CAFs. Single-sample Gene Set Enrichment Analysis (ssGSEA) results showed that GLS and MTF1 were highly expressed when fibroblasts proliferated at high enrichment levels. In addition, analysis of single-cell sequencing results suggested that OSCC cells with high expression of AFOC-DEGs were associated with OSCC metastasis. CONCLUSION: We found a close association between arecoline, cuproptosis, and CAFs, which might play an important role in the metastasis of OSCC.