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Single-cell analysis reveals the implication of vascular endothelial cell-intrinsic ANGPT2 in human intracranial aneurysm.
AIMS: While previous single-cell RNA sequencing (scRNA-seq) studies have attempted to dissect intracranial aneurysm (IA), the primary molecular mechanism for IA pathogenesis remains unknown. Here, we uncovered the alterations of cellular compositions, especially the transcriptome changes of vascular endothelial cells (ECs), in human IA. METHODS AND RESULTS: We performed scRNA-seq to compare the cell atlas of sporadic IA and the control artery. The transcriptomes of 43 462 cells were profiled for further analysis. In general, IA had increased immune cells (T/NK cells, B cells, myeloid cells, mast cells, neutrophils) and fewer vascular cells (ECs, vascular smooth muscle cells, and fibroblasts). Based on the obtained high-quantity and high-quality EC data, we found genes associated with angiogenesis in ECs from IA patients. By EC-specific expression of candidate genes in vivo, we observed the involvement of angpt2a in causing cerebral vascular abnormality. Furthermore, an IA zebrafish model mimicking the main features of human IA was generated through targeting pdgfrb gene, and knockdown of angpt2a alleviated the vascular dilation in the IA zebrafish model. CONCLUSION: By performing a landscape view of the single-cell transcriptomes of IA and the control artery, we contribute to a deeper understanding of the cellular composition and the molecular changes of ECs in IA. The implication of angiogenic regulator ANGPT2 in IA formation and progression, provides a novel potential therapeutical target for IA interventions.
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Crosstalk between Placental Trophoblast and Decidual Immune Cells in Recurrent Miscarriage.
Recurrent miscarriage (RM) is a pregnancy complication associated with dysregulation of the maternal-fetal interface. We aimed to identify dysfunctional interactions between trophoblast cells and decidual immune cells in RM. We downloaded single-cell RNA sequencing (scRNA-seq) datasets (GSE214607) from the Gene Expression Omnibus (GEO) datasets for further analysis using the R software. The data comprised of paired placental and decidual tissues, including those from patients diagnosed with RM and matched healthy controls. A total of 22976 cells were identified in 11 cell types, including trophoblasts, immune cells, and other cells. We divided trophoblast cells into three types and analyzed their interactions with decidual immune cells. Additionally, we re-clustered NK&T cells and macrophages, identified differentially expressed genes (DEGs), enriched their functions, and compared the cell interactions with trophoblast cells in each cell type. Our single-cell atlas of the maternal-fetal interface revealed alterations in the cellular organization of the decidua and placenta, cell type-specific transcriptome, and cell communication between immune and non-immune cells in RM, which are critical for illuminating the pathophysiology of RM.
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Integrated single-cell and bulk RNA sequencing analysis establishes a cancer associated fibroblast-related signature for predicting prognosis and therapeutic responses in neuroblastoma.
BACKGROUND: Cancer-associated fibroblasts (CAFs) greatly contribute to the growth, invasion, metastasis and drug resistance of neuroblastoma (NB). This study aimed to construct a CAF-related prognostic model and identify the immune status of patients with NB via single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq). METHODS: ScRNA-seq data of NB acquired from the Gene Expression Omnibus (GEO) database were used to identify cellular subpopulations. Bulk gene expression data were downloaded from GEO, The Cancer Genome Atlas (TCGA) and ArrayExpress databases and the prognostic model was constructed using univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) analyses. Differences in immune infiltration, therapeutic responses and signaling pathways between the high- and low-risk groups were investigated. Finally, immunohistochemistry was performed to evaluate the protein expressions and a nomogram based on the risk signature and clinical characteristics was constructed. RESULTS: ScRNA-seq data of eight NB samples were integrated to identify 253 marker genes for CAF. An eight-gene prognostic CAF-related signature was established based on the GEO data. The CAF model was strongly associated with immune infiltration, drug response and active signaling pathways in tumors. Univariate and multivariate Cox regression analyses verified that the CAF model was as an independent prognostic indicator, and a nomogram integrating the clinical signature and CAF-related risk signature was constructed for clinical prediction. CONCLUSIONS: The CAF-related signature can effectively predict the prognosis of NB and provide new genomic evidence for anti-CAF immunotherapeutic strategies.
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A pathology-to-single-cell framework links SPP1+ M2 macrophages with NETs-prone high-risk niches in HCC.
BACKGROUND: Neutrophil extracellular traps (NETs) facilitate hepatocellular carcinoma (HCC) progression, but the upstream cellular organizers and the histopathological correlates of NETosis-prone niches remain poorly defined. We aimed to build a pathology-to-single-cell framework to (i) quantify NETs-associated risk from routine whole-slide images (WSI) and (ii) nominate candidate organizer cells and mechanisms, focusing on SPP1+ M2 macrophages. METHODS: We integrated WSI, bulk transcriptomics, single-cell RNA-seq, spatial transcriptomics, and germline association data. NETs activity was quantified using gene-set scoring and aligned with WSI-derived morphology features (e.g. texture, stromal boundary disruption, and tumor–stroma interface complexity) to train and validate a prognostic model using regularized feature selection and survival machine learning. A 26,928-cell single-cell atlas was constructed to annotate macrophage states and neutrophil subsets, followed by trajectory inference to model macrophage polarization dynamics. Cell–cell communication was evaluated by ligand–receptor co-expression networks, and pathway/metabolic programs were inferred using multi-method enrichment and flux estimation. Spatial co-localization and neighborhood effects were assessed by deconvolution and spatial interaction modeling. Finally, network-based target prioritization was performed to highlight druggable nodes and candidate intervention pathways. RESULTS: The WSI-derived NETs risk score stratified overall survival in training and validation cohorts (HR ≈ 8.48 and ≈6.44; AUC > 0.78). Multi-omics integration prioritized SPP1 as a central hub. SPP1+ M2 macrophages and NETs+ neutrophils preferentially localized at the tumor–stroma interface, where inferred communication converged on OPN(SPP1)–CD44/integrins and ICAM1–β2-integrin axes with downstream FAK–PI3K–Akt and NF-κB/MAPK signaling. Metabolic inference suggested a shared hypoxia/glycolysis–lactate–glutathione/antioxidant program in SPP1+ M2 macrophages mirrored by NETs+ neutrophils, consistent with a NETosis-permissive niche. Germline mapping indicated an antagonistic association pattern for the SPP1+ M2 program. Network prioritization highlighted SRC, AKT1, and CEBPB and pathways including ECM–receptor interaction, FAK/PI3K–Akt, MAPK, and TNF/IL-17. CONCLUSIONS: Our framework links routine pathology morphology to NETs activity and nominates SPP1+ M2 macrophages as candidate organizers of NETosis-prone high-risk niches in HCC. Importantly, the proposed macrophage–NETs axis is supported by convergent multi-omics/spatial evidence but remains primarily associative and inference-based, not definitive causation. Future work should include functional validation (e.g. macrophage–neutrophil co-culture NETosis assays, SPP1/CD44/integrin or ICAM1–ITGB2 perturbation, and in vivo depletion/blockade studies), prospective multi-center evaluation of the WSI risk score, and testing whether this axis generalizes beyond HCC or is liver-specific. These results provide a quantitative pathology-based risk stratification approach and a set of mechanistically plausible, targetable signaling–metabolic nodes for therapeutic exploration.
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Evaluation of immune status in testis and macrophage polarization associated with testicular damage in patients with nonobstructive azoospermia.
OBJECTIVE: Immune cells residing in the testicular interstitial space form the immunological microenvironment of the testis. They are assumed to play a role in maintaining testicular homeostasis and immune privilege. However, the immune status and related cell polarization in patients with nonobstructive azoospermia (NOA) remains poorly characterized. System evaluation of the testis immunological microenvironment in NOA patients may help to reveal the mechanisms of idiopathic azoospermia. STUDY DESIGN: The gene expression patterns of immune cells in normal human testes were systematically analyzed by single-cell RNA sequencing (scRNA-seq) and preliminarily verification by the human protein atlas (HPA) online database. The immune cell infiltration profiles and immune status of patients with NOA was analyzed by single-sample gene set enrichment analysis (ssGSEA) and gene set variation analysis (GSVA) based on four independent public microarray datasets (GSE45885, GSE45887, GSE9210, and GSE145467), obtained from Gene Expression Omnibus (GEO) online database. The relationship between immune cells and spermatogenesis score was further analyzed by Spearman correlation analysis. Finally, immunohistochemistry (IHC) staining was performed to identify the main immune cell types and their polarization status in patients with NOA. RESULTS: Both scRNA-seq and HPA analysis showed that testicular macrophages represent the largest pool of immune cells in the normal testis, and also exhibit an attenuated inflammatory response by expressing high levels of tolerance proteins (CD163, IL-10, TGF-β, and VEGF) and reduced expression of TLR signaling pathway-related genes. Correlation analysis revealed that the testicular immune score and macrophages including M1 and M2 macrophages were significantly negatively correlated with spermatogenesis score in patients with NOA (GSE45885 and GSE45887). In addition, the number of M1 and M2 macrophages was significantly higher in patients with NOA (GSE9210 and GSE145467) than in normal testis. GSVA analysis indicated that the immunological microenvironment in NOA tissues was manifested by activated immune system and pro-inflammatory status. IHC staining results showed that the number of M1 and M2 macrophages was significantly higher in NOA tissues than in normal testis and negatively correlated with the Johnson score. CONCLUSION: Testicular macrophage polarization may play a vital role in NOA development and is a promising potential therapeutic target.
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Single-Cell RNA Transcriptome Helps Define the Limbal/Corneal Epithelial Stem/Early Transit Amplifying Cells and How Autophagy Affects This Population.
PURPOSE: Single-cell RNA-sequencing (scRNA-seq) was used to interrogate the relatively rare stem (SC) and early transit amplifying (TA) cell populations in limbal/corneal epithelia from wild-type and autophagy-compromised mice. METHODS: We conducted scRNA-seq on ocular anterior segmental tissue from wild-type and beclin 1-deficient (beclin1+/-) mice, using a 10X Gemomics pipeline. Cell populations were distinguished by t-distributed stochastic neighbor embedding. Seurat analysis was conducted to compare gene expression profiles between these two groups of mice. Differential protein expression patterns were validated by immunofluorescence staining and immunoblotting. RESULTS: Unbiased clustering detected 10 distinct populations: three clusters of mesenchymal and seven clusters of epithelial cells, based on their unique molecular signatures. A discrete group of mesenchymal cells expressed genes associated with corneal stromal SCs. We identified three limbal/corneal epithelial cell subpopulations designated as stem/early TA, mature TA, and differentiated corneal epithelial cells. Thioredoxin-interacting protein and PDZ-binding kinase (PBK) were identified as novel regulators of stem/early TA cell quiescence. PBK arrested corneal epithelial cells in G2/M phase of the cell cycle. Beclin1+/- mice displayed a decrease in proliferation-associated (Ki67, Lrig1) and stress-response (H2ax) genes. The most increased gene in beclin1+/- mice was transcription factor ATF3, which negatively regulates limbal epithelial cell proliferation. CONCLUSIONS: Establishment of a comprehensive atlas of genes expressed by stromal and epithelial cells from limbus and cornea forms the foundation for unraveling regulatory networks among these distinct tissues. Similarly, scRNA-seq profiling of the anterior segmental epithelia from wild-type and autophagy-deficient mice provides new insights into how autophagy influences proliferation in these tissues.
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Spatial and Single-Cell Investigations Illuminate Theragnostic value and Immune Landscape of Mitochondrial Dynamin-Like GTPase in Breast Cancer.
Background: As we delve into the intricate world of mitochondrial inner membrane proteins, particularly Optic Atrophy types 1 and 3 (OPA1/3), we uncover their pivotal role in maintaining mitochondrial dynamic equilibrium and fusion, crucial for cellular energy production and synthesis. Despite extensive scrutiny, the significance of OPA1/3 in breast cancer (BRCA) and its interplay with the immune microenvironment remain elusive. Materials and Methods: We meticulously sourced BRCA data from renowned repositories such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and the Human Protein Atlas (HPA), leveraging cutting-edge techniques including single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and pharmacogenomics. Through multifaceted data analysis, we endeavored to unravel the intricate role and potential value of OPA1/3 in BRCA tumorigenesis and progression. Results: Our investigation reveals a conspicuous upregulation of OPA1/3 expression in BRCA, correlating with dismal prognoses. Kaplan-Meier plot analysis underscores that heightened OPA1/3 levels are associated with poor survival rates. Both clinical specimens and biobank biopsies corroborate the elevated expression of OPA1/3 in breast cancer patients. Moreover, scRNA-seq unveils a strong correlation between OPA1/3 and macrophage infiltration in the BRCA immune milieu, alongside its association with the cellular communication network involving CXCL, TGFb, VEGF, and IL16. Conclusion: In light of these findings, OPA1/3 emerges as a promising contender for therapeutic targeting and as a potential diagnostic, prognostic, and survival biomarker in BRCA. The implications of our study underscore the pressing need to explore these novel biomarkers to enhance patient outcomes.
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Comprehensive analysis of nicotinamide metabolism-related signature for predicting prognosis and immunotherapy response in breast cancer.
BACKGROUND: Breast cancer (BC) is the most common malignancy among women. Nicotinamide (NAM) metabolism regulates the development of multiple tumors. Herein, we sought to develop a NAM metabolism-related signature (NMRS) to make predictions of survival, tumor microenvironment (TME) and treatment efficacy in BC patients. METHODS: Transcriptional profiles and clinical data from The Cancer Genome Atlas (TCGA) were analyzed. NAM metabolism-related genes (NMRGs) were retrieved from the Molecular Signatures Database. Consensus clustering was performed on the NMRGs and the differentially expressed genes between different clusters were identified. Univariate Cox, Lasso, and multivariate Cox regression analyses were sequentially conducted to develop the NAM metabolism-related signature (NMRS), which was then validated in the International Cancer Genome Consortium (ICGC) database and Gene Expression Omnibus (GEO) single-cell RNA-seq data. Further studies, such as gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, SubMap, and Immunophenoscore (IPS) algorithm, cancer-immunity cycle (CIC), tumor mutation burden (TMB), and drug sensitivity were performed to assess the TME and treatment response. RESULTS: We identified a 6-gene NMRS that was significantly associated with BC prognosis as an independent indicator. We performed risk stratification according to the NMRS and the low-risk group showed preferable clinical outcomes (P < 0.001). A comprehensive nomogram was developed and showed excellent predictive value for prognosis. GSEA demonstrated that the low-risk group was predominantly enriched in immune-associated pathways, whereas the high-risk group was enriched in cancer-related pathways. The ESTIMATE and CIBERSORT algorithms revealed that the low-risk group had a higher abundance of anti-tumor immunocyte infiltration (P < 0.05). Results of Submap, IPS, CIC, TMB, and external immunotherapy cohort (iMvigor210) analyses showed that the low-risk group were indicative of better immunotherapy response (P < 0.05). CONCLUSIONS: The novel signature offers a promising way to evaluate the prognosis and treatment efficacy in BC patients, which may facilitate clinical practice and management.
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FGFR4 and HER2 co-expression is associated with the proinflammatory tumor microenvironment in HR + breast cancer.
BACKGROUND: Dysregulated FGFR4 signaling has been associated with aggressive subtypes of breast cancers, characterized by HER2 enrichment or endocrine resistance. However, the biological functions of FGFR4 across breast cancer subtypes remain unclear. This study investigated the molecular characteristics of FGFR4-high tumors to inform potential therapeutic strategies. METHODS: This study analyzed clinicopathological characteristics and gene expression profile of 53 hormone receptor-positive (HR+) and 41 HR-negative (HR-) patients using the AmoyDx Master Panel. The results were validated using The Cancer Genome Atlas (TCGA) and single-cell RNA-seq datasets. RESULTS: The patients in the PUMCH cohort (n = 94) were stratified by HER2 and HR statuses and further stratified according to FGFR4 expression. FGFR4-high tumors showed no genomic differences but enriched immune activation pathways, specifically in HR+HER2-low/positive subgroups. HR+ tumors with co-expression of FGFR4 and HER2 exhibited increased immune infiltration (T cells, NK cells, M1 macrophages) and upregulated checkpoints (BTLA, CTLA4, HAVCR2, LAG3). Single-cell data confirmed elevated T-cell abundance in HR+HER2-high FGFR4-high cases. TCGA analysis linked high FGFR4 to prolonged disease-free survival (DFS) in HR+HER2-positive patients but reduced DFS in HR+HER2-zero patients. CONCLUSIONS: Co-expression of FGFR4 and HER2 is associated with a proinflammatory tumor microenvironment in HR+ breast cancer, suggesting immunotherapy potential. Further studies should explore therapeutic strategies to reshape the tumor immune microenvironment.
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Single-cell transcriptomic analysis reveals epithelial and microenvironmental heterogeneity in small cell carcinoma of the esophagus.
BACKGROUND: Small cell carcinoma of the esophagus (SCCE) is a rare and highly aggressive malignancy with limited therapeutic options and poor prognosis. The paucity of clinical specimens and lack of established experimental models have hindered a comprehensive understanding of its cellular heterogeneity and tumor microenvironment. METHODS: We performed single-cell RNA sequencing on SCCE samples, and integrated them with publicly available scRNA-seq datasets from esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and adjacent normal tissues (NT) from ESCC and EAC cases. An integrative transcriptomic analysis was conducted to identify cell types, infer malignant states, reconstruct differentiation trajectories, evaluate immune landscapes, and investigate fibroblast subtypes and cell-cell communication networks. RESULTS: SCCE tumors were characterized by a predominance of malignant epithelial cells and exhibited a profoundly immunosuppressed phenotype, with reduced immune infiltration and widespread downregulation of immune checkpoint genes. Malignant epithelial cells showed pronounced chromosomal instability and were classified into three transcriptionally distinct subtypes with divergent differentiation trajectories. The tumor microenvironment featured a complex stromal compartment, with enrichment of extracellular matrix fibroblasts (eCAFs) characterized by elevated ELF3 regulatory activity, and collagen-driven signaling predominantly mediated by inflammatory CAFs (iCAFs). SCCE also showed the most intricate cell-cell communication network among esophageal cancer subtypes. CONCLUSION: Our single-cell atlas offers a detailed view of the cellular heterogeneity and microenvironmental complexity of SCCE, highlighting its distinct tumor architecture, immune exclusion, and stromal reprogramming. These findings provide a valuable resource for understanding SCCE biology and form a basis for future mechanistic and exploratory biological investigations.