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Investigating the basis of lineage decisions and developmental trajectories in the dorsal spinal cord through pseudotime analyses.
UNLABELLED: Dorsal interneurons (dIs) in the spinal cord encode the perception of touch, pain, heat, itch, and proprioception. While previous studies using genetic strategies in animal models have revealed important insights into dI development, the molecular details by which dIs arise as distinct populations of neurons remain incomplete. We have developed a resource to investigate dI fate specification by combining a single-cell RNA-Seq atlas of mouse ESC-derived dIs with pseudotime analyses. To validate this in silico resource as a useful tool, we used it to first identify novel genes that are candidates for directing the transition states that lead to distinct dI lineage trajectories, and then validated them using in situ hybridization analyses in the developing mouse spinal cord in vivo . We have also identified a novel endpoint of the dI5 lineage trajectory and found that dIs become more transcriptionally homogenous during terminal differentiation. Together, this study introduces a valuable tool for further discovery about the timing of gene expression during dI differentiation and demonstrates its utility clarifying dI lineage relationships. SUMMARY STATEMENT: Pseudotime analyses of embryonic stem cell-derived dorsal spinal interneurons reveals both novel regulators and lineage relationships between different interneuron populations.
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Multi-Omics Characterization of Tumor Microenvironment Heterogeneity and Immunotherapy Resistance Through Cell States-Based Subtyping in Bladder Cancer.
Due to the strong heterogeneity of bladder cancer (BC), there is often substantial variation in the prognosis and efficiency of immunotherapy among BC patients. For the precision treatment and assessment of prognosis, the subtyping of BC plays a critical role. Despite various subtyping methods proposed previously, most of them are based on a limited number of molecules, and none of them is developed on the basis of cell states. In this study, we construct a single-cell atlas by integrating single cell RNA-seq, RNA microarray, and bulk RNA-seq data to identify the absolute proportion of 22 different cell states in BC, including immune and nonimmune cell states derived from tumor tissues. To explore the heterogeneity of BC, BC was identified into four different subtypes in multiple cohorts using an improved consensus clustering algorithm based on cell states. Among the four subtypes, C1 had median prognosis and best overall response rate (ORR), which characterized an immunosuppressive tumor microenvironment. C2 was enriched in epithelial-mesenchymal transition/invasion, angiogenesis, immunosuppression, and immune exhaustion. Surely, C2 performed the worst in prognosis and ORR. C3 with worse ORR than C2 was enriched in angiogenesis and almost nonimmune exhaustion. Displaying an immune effective environment, C4 performed the best in prognosis and ORR. We found that patients with just an immunosuppressive environment are suitable for immunotherapy, but patients with an immunosuppressive environment accompanied by immune exhaustion or angiogenesis may resist immunotherapy. Furthermore, we conducted exploration into the heterogeneity of the transcriptome, mutational profiles, and somatic copy-number alterations in four subtypes, which could explain the significant differences related to cell states in prognosis and ORR. We also found that PD-1 in immune and tumor cells could both influence ORR in BC. The level of TGFβ in a cell state can be opposite to the overall level in the tissues, and the level in a specific cell state could predict ORR more accurately. Thus, our work furthers the understanding of heterogeneity and immunotherapy resistance in BC, which is expected to assist clinical practice and serve as a supplement to the current subtyping method from a novel perspective of cell states.
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Single cell dual-omic atlas of the human developing retina.
The development of the retina is under tight temporal and spatial control. To gain insights into the molecular basis of this process, we generate a single-nuclei dual-omic atlas of the human developing retina with approximately 220,000 nuclei from 14 human embryos and fetuses aged between 8 and 23-weeks post-conception with matched macular and peripheral tissues. This atlas captures all major cell classes in the retina, along with a large proportion of progenitors and cell-type-specific precursors. Cell trajectory analysis reveals a transition from continuous progression in early progenitors to a hierarchical development during the later stages of cell type specification. Both known and unrecorded candidate transcription factors, along with gene regulatory networks that drive the transitions of various cell fates, are identified. Comparisons between the macular and peripheral retinae indicate a largely consistent yet distinct developmental pattern. This atlas offers unparalleled resolution into the transcriptional and chromatin accessibility landscapes during development, providing an invaluable resource for deeper insights into retinal development and associated diseases.
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An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus.
Cell types in the hippocampus with unique morphology, physiology and connectivity serve specialized functions associated with cognition and mood. These cell types are spatially organized, necessitating molecular profiling strategies that retain cytoarchitectural organization. Here we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from anterior human hippocampus in ten adult neurotypical donors. Using non-negative matrix factorization (NMF) and label transfer, we integrated these data by defining gene expression patterns within the snRNA-seq data and then inferring expression in the SRT data. These patterns captured transcriptional variation across neuronal cell types and indicated spatial organization of excitatory and inhibitory postsynaptic specializations. Leveraging the NMF and label transfer approach with rodent datasets, we identified putative patterns of activity-dependent transcription and circuit connectivity in the human SRT dataset. Finally, we characterized the spatial organization of NMF patterns corresponding to pyramidal neurons and identified regionally-specific snRNA-seq clusters of the retrohippocampus, subiculum and presubiculum. To make this molecular atlas widely accessible, raw and processed data are freely available, including through interactive web applications.
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Multi-omics identification and functional validation of signal regulatory protein gamma as a prognostic biomarker and immune regulator in head and neck squamous cell carcinoma.
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) comprises biologically diverse tumors, and durable responses to immune-checkpoint blockade are achieved by only a subset of patients. There remains a need for markers that connect clinical outcome with malignant-cell phenotypes and tissue-level immune organization. METHODS: We integrated The Cancer Genome Atlas HNSCC cohort (TCGA-HNSC), five Gene Expression Omnibus (GEO) validation cohorts, single-cell RNA sequencing, Visium spatial transcriptomics, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq)-informed protein-potential inference, pharmacogenomic screening, genetic-risk analysis and experimental validation. A reconstructed 296-pipeline survival modelling framework was used to prioritize prognostic hub genes across validation-cohort-specific analyses. RESULTS: SIRPG was repeatedly ranked among the top ten selected genes in all five validation cohorts. At single-cell resolution, SIRPG-high tumor cells showed stronger malignant-cell features, immune-inhibitory and metabolic programs, Scissor-positive risk association, CLCA2/P53-related perturbation signals and inferred SIRPG-CD47/signal regulatory protein (SIRP) communication. Spatial analyses placed this axis within an immune-checkpoint-coupled niche, supported by Maxspin/multiview intercellular spatial modelling (MISTy) spatial coupling, communication analysis by optimal transport (COMMOT)-inferred CD47-SIRPG communication and scProTrans-inferred CD47/SIRPG protein-potential overlap. Functionally, SIRPG knockdown reduced HNSCC cell viability and increased apoptosis, whereas re-expression of short hairpin RNA (shRNA)-resistant SIRPG restored the CLCA2-BAX/BCL2 protein response. CONCLUSION: Together, these findings identify SIRPG as an immune-related prognostic hub and context-dependent tumor-cell regulator associated with apoptosis, immune communication and spatial microenvironmental organization in HNSCC.
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MSR1 + macrophages passivate antitumor immunity by inducing ITM2A + CD4T exhaustion differentiation.
BACKGROUND AND AIMS: Immune-checkpoint inhibitors target the membrane protein; however, the role of membrane proteins in antitumor immunity remains poorly elucidated. In this study, we aimed to explore the role of membrane proteins and unearth potential membrane proteins that can be targeted. APPROACH AND RESULTS: We initially screened prognosis-related membrane proteins based on The Cancer Genome Atlas Program and International Cancer Genome Consortium databases. Whole-gene, T-cell-specific or CD8T-cell-specific integral membrane protein 2A (ITM2A) knockout mice were constructed and used for orthotopic transplantation or as plasmid-derived spontaneous hepatocellular carcinoma (HCC) models to explore the role of ITM2A in the tumor microenvironment (TME). Through single-cell RNA sequencing (scRNA-seq), TimiGP analysis, molecular dynamics simulations, and biochemical experiments, the molecular mechanisms underlying the MSR1-ITM2A-TCR signaling regulatory axis were explored. Finally, bioengineering technologies were used to design and construct a new CD4T-targeted antibody-drug conjugate (ADC).High ITM2A expression in HCC indicated a superior prognosis, which was associated with richer immune cell infiltration in the TME. The results of the scRNA-seq of the HCC model in genetically knocked-out mice suggest that ITM2A influences the TCR signaling of tumor-infiltrating lymphocytes in the TME. This inference was confirmed in conditional ITM2A knockout mice. MSR1 + macrophages induced CD4T exhaustion by disrupting the ITM2A-ZAP70 axis during TCR activation. ADC (ZEA-αCD4) treatment effectively inhibited tumor growth, independent of the classical αPDL1 immunotherapy. CONCLUSIONS: MSR1 + macrophages promote tumor-infiltrating ITM2A + CD4T exhaustion differentiation by regulating the ITM2A-ZAP70 axis. ZEA-αCD4 specifically targeted the MSR1-ITM2A interaction to activate antitumor immunity and improve the efficacy of αPDL1 immunotherapy.
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BCAT1 mediates the carcinogenic effects of environmental bisphenol exposure: mechanistic discoveries in osteosarcoma and pan-cancer analysis.
Bisphenols (including BPA, BPF, BPS, BPAF and TBBPA) are ubiquitous environmental endocrine disruptors linked to increased risk of multiple malignancies, yet their carcinogenic mechanisms remain poorly understood. To address this gap, the present study aimed to elucidate how bisphenols drive osteosarcoma initiation and progression, identify core mediating targets, and explore their pan-cancer relevance. We integrated network toxicology with osteosarcoma transcriptome datasets to screen hub genes, validated candidates via independent cohorts and machine learning, and pinpointed the core target through combined SHapley Additive Explanations (SHAP) and Weighted Gene Co-expression Network Analysis (WGCNA). Using data from The Cancer Genome Atlas (TCGA), we analyzed the target's association with osteosarcoma patient survival, while reverse transcription quantitative polymerase chain reaction (RT-qPCR), RNA sequencing (RNA-seq), and Western blotting confirmed its differential expression in osteosarcoma cell lines versus normal osteoblasts. Additionally, we performed simulated BCAT1 gene knockout using scTenifoldKnk to investigate its regulatory effects on downstream gene networks. Molecular docking and all-atom molecular dynamics simulations assessed bisphenol-target binding affinity, complemented by comprehensive pan-cancer analyses of public omics databases. Bioinformatic analyses identified branched-chain amino acid transaminase 1 (BCAT1) as the key regulatory gene, with experimental validation confirming its marked upregulation in osteosarcoma cells. All five bisphenols exhibited high binding affinity for BCAT1 in structural simulations, and pan-cancer analysis revealed BCAT1 overexpression in multiple solid tumors, correlating with unfavorable clinical outcomes. Collectively, these findings suggest that bisphenols may act as potential regulators of BCAT1, with implications for tumor progression, though further experimental validation is required to confirm the actual enzymatic activity modulation and carcinogenic effects.
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A human cell atlas of fetal gene expression.
The gene expression program underlying the specification of human cell types is of fundamental interest. We generated human cell atlases of gene expression and chromatin accessibility in fetal tissues. For gene expression, we applied three-level combinatorial indexing to >110 samples representing 15 organs, ultimately profiling ~4 million single cells. We leveraged the literature and other atlases to identify and annotate hundreds of cell types and subtypes, both within and across tissues. Our analyses focused on organ-specific specializations of broadly distributed cell types (such as blood, endothelial, and epithelial), sites of fetal erythropoiesis (which notably included the adrenal gland), and integration with mouse developmental atlases (such as conserved specification of blood cells). These data represent a rich resource for the exploration of in vivo human gene expression in diverse tissues and cell types.
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DIANA-miTED: a microRNA tissue expression database.
microRNAs (miRNAs) are short (∼23nt) single-stranded non-coding RNAs that act as potent post-transcriptional gene expression regulators. Information about miRNA expression and distribution across cell types and tissues is crucial to the understanding of their function and for their translational use as biomarkers or therapeutic targets. DIANA-miTED is the most comprehensive and systematic collection of miRNA expression values derived from the analysis of 15 183 raw human small RNA-Seq (sRNA-Seq) datasets from the Sequence Read Archive (SRA) and The Cancer Genome Atlas (TCGA). Metadata quality maximizes the utility of expression atlases, therefore we manually curated SRA and TCGA-derived information to deliver a comprehensive and standardized set, incorporating in total 199 tissues, 82 anatomical sublocations, 267 cell lines and 261 diseases. miTED offers rich instant visualizations of the expression and sample distributions of requested data across variables, as well as study-wide diagrams and graphs enabling efficient content exploration. Queries also generate links towards state-of-the-art miRNA functional resources, deeming miTED an ideal starting point for expression retrieval, exploration, comparison, and downstream analysis, without requiring bioinformatics support or expertise. DIANA-miTED is freely available at http://www.microrna.gr/mited.
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Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas.
OBJECTIVE: To better understand the immune microenvironment of pancreatic ductal adenocarcinomas (PDACs), here we explored the relevance of T and B cell compartmentalisation into tertiary lymphoid structures (TLSs) for the generation of local antitumour immunity. DESIGN: We characterised the functional states and spatial organisation of PDAC-infiltrating T and B cells using single-cell RNA sequencing (scRNA-seq), flow cytometry, multicolour immunofluorescence, gene expression profiling of microdissected TLSs, as well as in vitro assays. In addition, we performed a pan-cancer analysis of tumour-infiltrating T cells using scRNA-seq and sc T cell receptor sequencing datasets from eight cancer types. To evaluate the clinical relevance of our findings, we used PDAC bulk RNA-seq data from The Cancer Genome Atlas and the PRINCE chemoimmunotherapy trial. RESULTS: We found that a subset of PDACs harbours fully developed TLSs where B cells proliferate and differentiate into plasma cells. These mature TLSs also support T cell activity and are enriched with tumour-reactive T cells. Importantly, we showed that chronically activated, tumour-reactive T cells exposed to fibroblast-derived TGF-β may act as TLS organisers by producing the B cell chemoattractant CXCL13. Identification of highly similar subsets of clonally expanded CXCL13 + tumour-infiltrating T cells across multiple cancer types further indicated a conserved link between tumour-antigen recognition and the allocation of B cells within sheltered hubs in the tumour microenvironment. Finally, we showed that the expression of a gene signature reflecting mature TLSs was enriched in pretreatment biopsies from PDAC patients with longer survival after receiving different chemoimmunotherapy regimens. CONCLUSION: We provided a framework for understanding the biological role of PDAC-associated TLSs and revealed their potential to guide the selection of patients for future immunotherapy trials.