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The EBV Gastric Cancer Resource (EBV-GCR): A Suite of Tools for Investigating EBV-Associated Human Gastric Carcinogenesis.
Epstein-Barr virus (EBV) causes lifelong infection in over 90% of the world's population. EBV infection leads to several types of B cell and epithelial cancers due to the viral reprogramming of host-cell growth and gene expression. EBV is associated with 10% of stomach/gastric adenocarcinomas (EBVaGCs), which have distinct molecular, pathological, and immunological characteristics compared to EBV-negative gastric adenocarcinomas (EBVnGCs). Publicly available datasets, such as The Cancer Genome Atlas (TCGA), contain comprehensive transcriptomic, genomic, and epigenomic data for thousands of primary human cancer samples, including EBVaGCs. Additionally, single-cell RNA-sequencing data are becoming available for EBVaGCs. These resources provide a unique opportunity to explore the role of EBV in human carcinogenesis, as well as differences between EBVaGCs and their EBVnGC counterparts. We have constructed a suite of web-based tools called the EBV Gastric Cancer Resource (EBV-GCR), which utilizes TCGA and single-cell RNA-seq data and can be used for research related to EBVaGCs. These web-based tools allow investigators to gain in-depth biological and clinical insights by exploring the effects of EBV on cellular gene expression, associations with patient outcomes, immune landscape features, and differential gene methylation, featuring both whole-tissue and single-cell analyses.
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Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment.
Cancer immunotherapy has revolutionized cancer treatment, and it relies heavily on the comprehensive understanding of the immune landscape of the tumor microenvironment (TME). Here, we obtain a detailed immune cell atlas of esophageal squamous cell carcinoma (ESCC) at single-cell resolution. Exhausted T and NK cells, regulatory T cells (Tregs), alternatively activated macrophages and tolerogenic dendritic cells are dominant in the TME. Transcriptional profiling coupled with T cell receptor (TCR) sequencing reveal lineage connections in T cell populations. CD8 T cells show continuous progression from pre-exhausted to exhausted T cells. While exhausted CD4, CD8 T and NK cells are major proliferative cell components in the TME, the crosstalk between macrophages and Tregs contributes to potential immunosuppression in the TME. Our results indicate several immunosuppressive mechanisms that may be simultaneously responsible for the failure of immuno-surveillance. Specific targeting of these immunosuppressive pathways may reactivate anti-tumor immune responses in ESCC.
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Cell type transcriptome atlas for the planarian Schmidtea mediterranea.
The transcriptome of a cell dictates its unique cell type biology. We used single-cell RNA sequencing to determine the transcriptomes for essentially every cell type of a complete animal: the regenerative planarian Schmidtea mediterranea. Planarians contain a diverse array of cell types, possess lineage progenitors for differentiated cells (including pluripotent stem cells), and constitutively express positional information, making them ideal for this undertaking. We generated data for 66,783 cells, defining transcriptomes for known and many previously unknown planarian cell types and for putative transition states between stem and differentiated cells. We also uncovered regionally expressed genes in muscle, which harbors positional information. Identifying the transcriptomes for potentially all cell types for many organisms should be readily attainable and represents a powerful approach to metazoan biology.
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Morphological diversity of single neurons in molecularly defined cell types.
Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types1,2, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits.
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Therapeutic Potential of CLDN Family Proteins in Ovarian Cancer: Emerging Biomarkers and Targets.
BACKGROUND: Claudins (CLDNs), key components of tight junctions, are dysregulated in various cancers. However, the roles and therapeutic potential of specific CLDN family members-particularly CLDN6, CLDN9, and CLDN10-in ovarian cancer (OC) remain incompletely defined. To address this gap, we conducted a comprehensive analysis of the CLDN family to identify novel diagnostic and prognostic biomarkers as well as potential therapeutic targets for OC. METHODS: Gene expression profiles and corresponding clinical data from The Cancer Genome Atlas ovarian cancer cohort (TCGA-OV) and two Gene Expression Omnibus (GEO) datasets (GSE18520, GSE26712) were analyzed. Differential expression of CLDN genes between OC and normal tissues was evaluated using R with appropriate bioinformatics packages (e.g., limma). Logistic regression models were employed to calculate odds ratios (ORs), and receiver operating characteristic (ROC) curves were generated across all datasets to identify consistently dysregulated CLDNs associated with OC. Prognostic hazard ratios (HRs) for these CLDNs were extracted from the Kaplan-Meier Plotter (KM Plotter) database and synthesized using a random-effects model to assess their associations with overall survival. Intersection analysis was performed to identify CLDNs exhibiting both significant differential expression and prognostic significance. Candidate targets underwent comprehensive validation, including single-cell RNA sequencing (scRNA-seq) to characterize cell-type-specific expression patterns. Notably, Key findings regarding CLDN6 were further validated by immunohistochemistry (IHC) on an independent tissue microarray (TMA), as well as functional assays in OC cell lines following siRNA-mediated knockdown. These included transwell invasion, wound healing (scratch) test, and measurements of mitochondrial depolarization, reactive oxygen species (ROS) accumulation, cell cycle arrest, and apoptosis. RESULTS: CLDN6, CLDN9, and CLDN10 were consistently and significantly upregulated in OC compared to normal tissues across all datasets. Single-cell RNA sequencing revealed that CLDN6 and CLDN10 were predominantly expressed in malignant epithelial cell subsets, a pattern associated with aggressive tumor phenotypes. Meta-analysis of HRs showed that HR >1 in CLDN6 and HR <1 in CLDN10. Although CLDN10 is highly expressed in tumor cells, its hazard ratio (HR) is less than 1, and the underlying mechanism of this gene remains unclear. Experiments have confirmed that CLDN6 is closely associated with tumor invasion. Computational analysis, meta-analysis, and single-cell data collectively confirm that only CLDN6 is a clearly defined gene closely associated with tumor progression, a finding subsequently validated by experimental results. Notably, the combined signature comprising CLDN6, CLDN9, and CLDN10 exhibited superior diagnostic performance, with higher area under the curve (AUC) values in ROC analysis, compared to individual CLDNs or established OC biomarkers such as carbohydrate antigen 125 (CA125), human epididymis 4 (HE4), carcinoembryonic antigen (CEA), and alpha-fetoprotein (AFP). The signature also showed enhanced prognostic discrimination, as indicated by time-dependent ROC analysis. Protein overexpression of these targets was validated by IHC and Western blot. Functional assays further demonstrated that siRNA-mediated knockdown of CLDN6 significantly inhibited the proliferation of OC cells, promoted cell apoptosis, increased production of ROS, induced G1 phase arrest, inhibited cell invasion and migration in vitro. Furthermore, western blot analysis identified that knockdown of CLDN6 repressed the Wnt/β-catenin pathway. Nude mice experiments indicated that CLDN6 knockdown in OC cells dramatically suppresses the tumor growth and lung metastasis in vivo. CONCLUSIONS: CLDN6, CLDN9, and CLDN10 are critically involved in the pathogenesis and progression of OC. A biomarker panel combining these three claudins demonstrates superior diagnostic and prognostic performance compared to individual markers and established clinical biomarkers such as CA125 and HE4. Notably, functional evidence indicates that CLDN6 plays a pivotal role in regulating malignant phenotypes, highlighting its potential as a novel therapeutic target. These findings collectively support the clinical utility of the CLDN6/9/10 axis as both a non-invasive biomarker signature and a promising avenue for targeted intervention in ovarian cancer.
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Cathepsin H as a causal risk factor and therapeutic target in proliferative diabetic retinopathy.
BACKGROUND: Cathepsins, key lysosomal proteases, have been linked to diabetic retinopathy (DR) pathogenesis, but their causal role and therapeutic potential remain unclear. METHODS: We used bidirectional Mendelian randomization (MR) to explore causal relationships between cathepsins and DR stages, with validation by multivariable MR, Bayesian weighted MR, and colocalization analysis. Single-cell RNA sequencing (scRNA-seq) characterized cellular expression of relevant cathepsins in DR patients and mice. Candidate inhibitors were screened via the Proteomics Drug Atlas, followed by molecular docking and dynamics simulating their binding stability. Cellular experiments (CCK-8, scratch assay, LysoTracker staining) were performed to evaluate drug efficacy. RESULTS: Cathepsin H (CtsH) showed a causal association with proliferative DR (PDR) (IVW: p = 0.01, OR = 1.059), which was confirmed by multivariable and Bayesian MR. Colocalization identified shared genetic variants between CtsH and PDR (PP.H4 = 99.99%). ScRNA-seq revealed CtsH upregulation in monocytes of DR patients’ peripheral blood mononuclear cells and in retinal macroglia/endothelial cells of DR mice. Molecular docking demonstrated stable binding of SSR 69071 and PF429242 to CtsH (binding energies: −7.7 and −6.6 kcal/mol), with 100-ns dynamics confirming complex stability. In vitro, both compounds inhibited endothelial migration and wound healing in a time- and dose-dependent manner at safe concentrations (SSR 69071 ≤ 1 μM; PF429242 ≤ 10 μM), while PF429242 additionally increased lysosomal area. CONCLUSIONS: Elevated CtsH is an independent causal risk factor for PDR. The SSR 69071 and PF429242 exhibit promising inhibitory effects, supporting CtsH as both a biomarker and therapeutic target for PDR.
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Ageing hallmarks exhibit organ-specific temporal signatures.
Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.
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The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration.
Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac with a high glycolytic flux dominate the early injury response and rapidly give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood-nerve barrier, proliferation of endoneurial and perineurial stromal cells, and entry of opsonizing serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing, identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with Sarm1-/- mice, in which Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in Sarm1-/- mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand-receptor interactions. Our longitudinal analysis represents a new resource for neural tissue regeneration, reveals location- specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/.
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Coordinated transcriptional shifts in microglia and oligodendrocytes from neurodevelopment to inflammaging.
Glial cells shape brain development and aging, yet whether distinct glial lineages undergo coordinated lifespan transitions remains unclear. Although microglial aging states and oligodendrocyte vulnerability in neurodegeneration are well described, it remains unclear whether these programs evolve independently or in a temporally related manner. Here, we analyzed Mouse Cell Atlas single-cell RNA-seq data spanning embryogenesis to 24 months. Microglia and oligodendrocytes were the most transcriptionally dynamic glial populations, whereas astrocyte module activity was primarily observed during development. Microglia and oligodendrocytes exhibited similar late-life increases in inflammatory and senescence-associated modules, supported by cross-correlation (Pearson r ≈ 0.98; Max_CCF ≈ 0.98), dynamic time warping (DTW ≈ 6.16), and a large effect size (Cohen's d ≈ 11.08). These patterns were also supported by mixed glial contexts (p = 1.85 × 10⁻³). Together, these results identify a parallel transcriptional shift in microglia and oligodendrocytes from neurodevelopment to inflammaging and suggest that shared temporal programs across glial lineages may contribute to neurodegenerative vulnerability. This quantitative framework for assessing temporal similarity may be broadly applicable to other biological systems involving dynamic cellular state transitions.
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Single-cell analysis of TIGD genes in hepatocellular carcinoma: Prognostic value and functional characterization.
BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive cancer with limited therapies. Although transposable element-derived genes are increasingly linked to tumorigenesis, the role of the TIGD family in HCC remains unclear. This study examined the expression, clinical significance, and stemness-related features of TIGDs in HCC, emphasizing their prognostic and therapeutic potential. METHOD: TIGD expression was analyzed using TCGA data via GEPIA2, cBioPortal, and Kaplan-Meier Plotter, with protein validation from the Human Protein Atlas. Single-cell RNA-seq data (GSE242889) were used to examine TIGD expression across hepatic cell types. Survival and Cox regression analyses assessed prognostic value, while functional enrichment and immune infiltration analyses explored biological roles. TIGD5-high and TIGD5-low epithelial subsets were compared for functional features and cell-cell communication. RESULTS: TIGD1, 3, 4, 5, 6, and 7 were significantly upregulated in HCC. High TIGD4, TIGD5, and TIGD6 expression correlated with poorer overall survival and served as independent prognostic markers. TIGD5 exhibited the broadest and highest expression across immune and stromal compartments. Stratification of epithelial cells into TIGD5-high and TIGD5-low subsets revealed distinct functional phenotypes: TIGD5-high cells showed enrichment in extracellular matrix organization, growth factor signaling, and immune regulatory pathways, with enhanced communication probability within the tumor microenvironment. Notably, TIGD5+ epithelial cells demonstrated increased interaction strength and MIF signaling pathway engagement compared to TIGD5- counterparts. Functional analyses indicated roles in RNA splicing, DNA replication, and cell-cycle regulation. TIGDs also showed associations with immune infiltration, particularly Th2 cells. CONCLUSION: TIGD4, TIGD5, and TIGD6 exhibit oncogenic potential and may serve as prognostic biomarkers and therapeutic targets in HCC. Their stem-cell-associated expression highlights a novel connection between transposable element-derived genes and liver cancer stemness.