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Single-cell spatial transcriptional profiling of pancreatic ductal adenocarcinoma uncovers key immune-modulating and pro-metastatic mechanisms.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by profound tumor microenvironment (TME) heterogeneity and therapeutic resistance. However, the cellular dynamics, spatial architecture, and molecular networks driving progression from primary tumors (PTs) to hepatic metastases (HMs) remain incompletely understood. Here, we performed high-definition single-cell spatial transcriptomics using Xenium In Situ (5K) on formalin-fixed paraffin-embedded (FFPE) matched PDAC PTs and HMs, generating a single-cell spatial atlas encompassing more than 900,000 resolved cells. Integrated analysis with single-cell RNA sequencing revealed distinct cellular composition, spatial organization, and cell-cell communication patterns between PTs and HMs. Hypoxia and genomic instability were identified as core drivers of tumor cell plasticity toward a basal-like phenotype, while cancer-associated fibroblasts (CAFs) further shaped malignant cell fate. Compared with stroma-rich PTs, HMs displayed spatial immune-stromal remodeling and formed an immunogenic invasive border with actionable therapeutic vulnerabilities. We further identified functionally specialized macrophage subsets that spatially orchestrate pro-metastatic programs: TREM2+ macrophages drive tumor vascular remodeling, whereas MMP12+ macrophages promote CAF-mediated extracellular matrix (ECM) reorganization to facilitate metastasis. Moreover, CXCL9/10+ cells recruit and activate CD8+ T cells, and ectopic expression of Cxcl9/10 significantly sensitizes PDAC to immune checkpoint blockade in immunocompetent mouse models. Collectively, our study delineates the spatially coordinated tumor-stromal-immune ecosystem that sustains PDAC progression and metastasis, unveils novel immune-modulating and pro-metastatic mechanisms, and provides targetable vulnerabilities to improve immunotherapy for metastatic PDAC.
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Decoding the Mechanisms of Hepatocellular Carcinoma Cancer Stem Cells and Identifying Potential Therapeutic Strategies Based on Single-cell Omics.
BACKGROUND/AIM: Cancer stem cells (CSCs) play key roles in hepatocellular carcinoma (HCC) initiation, progression, therapeutic resistance, and recurrence, yet their cellular and spatial heterogeneity remains poorly understood. This study aimed to systematically characterize HCC-associated CSCs and identify prognostic biomarkers and potential therapeutic strategies using single-cell omics. MATERIALS AND METHODS: Single-cell RNA sequencing and spatial transcriptomics data were obtained from HCCDB v2.0. Malignant cells were re-clustered using Harmony-based batch correction, followed by uniform manifold approximation and projection (UMAP) and Louvain clustering. Copy number variation analysis validated malignant identities. CSC-associated molecular features were characterized using differential expression, gene regulatory network analysis (SCENIC), pathway enrichment (GSVA), pseudotime trajectory inference (Monocle, CytoTRACE2), and cell-cell communication analysis (CellChat). CSC-specific genes were integrated with GEO survival datasets (GSE76427, GSE14520) to construct a prognostic model, and potential CSC-targeting compounds were predicted using Connectivity Map. RESULTS: Six malignant subpopulations were identified, including a progenitor-like CSC subset expressing EPCAM, SOX9, and SOX4. Spatial transcriptomics revealed CSC enrichment at the tumor-stroma interface. CSCs exhibited strong stemness, metabolic plasticity, and invasive potential, with activation of WNT/β-catenin, TGF-β, Notch, EMT, MYC, and mTORC1 pathways. Key transcription factors (TEAD2, SOX4, HNF1B, KLF7) were identified. A 12-gene CSC-derived signature stratified patients into distinct risk groups with significantly different overall survival. Several candidate compounds, including fluspirilene, genistein, and daunorubicin, showed potential CSC-suppressive activity. CONCLUSION: This study provides a comprehensive single-cell-based atlas of CSCs in HCC, highlighting their spatial niches, regulatory programs, and clinical relevance. The identified prognostic signature and candidate drugs offer promising avenues for CSC-targeted therapies.
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Single-cell profiling of natural killer/T-cell lymphoma reveals stratified immune features and potential therapeutic implications.
Tumor cell heterogeneity and interactions with the immune microenvironment play a key role in the progression and therapeutic efficacy of natural killer/T-cell lymphoma (NKTCL). We perform single-cell RNA sequencing analysis of 63 samples, integrating spatial transcriptomics, bulk transcriptomics, proteomics, and metabolomics to dissect inter- and intra-tumoral heterogeneity. Four meta-programs (MP) are identified, including MP1 (immune-responsive), MP2 (proliferative), MP3 (inflammatory), and MP4 (metabolic), each linked to distinct molecular and immune features. MP1 exhibits an immune-exhausted tumor microenvironment and high programmed death-ligand 1 expression, suggesting a potential response to immune checkpoint blockade. MP2 shows an immune-desert phenotype with elevated HDAC2 and MKI67 expression, indicating epigenetic regulation in tumor proliferation. MP3 is characterized by a myeloid-dominant tumor microenvironment, JAK/STAT pathway activation, and an aggressive clinical course. MP4 exhibits a distinct amino acid metabolic profile and enriched tertiary lymphoid structures. Collectively, our study provides a high-resolution molecular atlas of NKTCL heterogeneity, offering insights into patient stratification and potential avenues for future therapeutic development.
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Single-Cell Transcriptome Analysis Reveals Development-Specific Networks at Distinct Synchronized Antral Follicle Sizes in Sheep Oocytes.
The development of the ovarian antral follicle is a complex, highly regulated process. Oocytes orchestrate and coordinate the development of mammalian ovarian follicles, and the rate of follicular development is governed by a developmental program intrinsic to the oocyte. Characterizing oocyte signatures during this dynamic process is critical for understanding oocyte maturation and follicular development. Although the transcriptional signature of sheep oocytes matured in vitro and preovulatory oocytes have been previously described, the transcriptional changes of oocytes in antral follicles have not. Here, we used single-cell transcriptomics (SmartSeq2) to characterize sheep oocytes from small, medium, and large antral follicles. We characterized the transcriptomic landscape of sheep oocytes during antral follicle development, identifying unique features in the transcriptional atlas, stage-specific molecular signatures, oocyte-secreted factors, and transcription factor networks. Notably, we identified the specific expression of 222 genes in the LO, 8 and 6 genes that were stage-specific in the MO and SO, respectively. We also elucidated signaling pathways in each antral follicle size that may reflect oocyte quality and in vitro maturation competency. Additionally, we discovered key biological processes that drive the transition from small to large antral follicles, revealing hub genes involved in follicle recruitment and selection. Thus, our work provides a comprehensive characterization of the single-oocyte transcriptome, filling a gap in the mapping of the molecular landscape of sheep oogenesis. We also provide key insights into the transcriptional regulation of the critical sizes of antral follicular development, which is essential for understanding how the oocyte orchestrates follicular development.
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Single-cell transcriptome analysis in ovarian steroid cell tumors-not otherwise specified.
BACKGROUND: Ovarian steroid cell tumors-not otherwise specified (SCT-NOS) is a rare category of sex cord-stromal tumor, however, its pathophysiology is unclear. A comprehensive cellular atlas of ovarian SCT-NOS remains lacking. METHODS: We reported a case of a 41-year-old woman with hyperandrogenism for whom histopathological analysis confirmed the presence of ovarian SCT-NOS. This study utilized single-cell RNA sequencing in a case of ovarian SCT-NOS. RESULTS: Seven cell types, including four keratin 19 (KRT19)⁺ steroidogenic cell subtypes, were identified in the tumor microenvironment. We detected aberrant gene expression across various cell types in ovarian SCT-NOS. KRT19⁺ steroidogenic cells were enriched in genes involved in ovarian steroidogenesis and steroid biosynthesis pathways, which was consistent with the pathobiology of hyperandrogenism. Moreover, we revealed distinct immune cell types in the tumor microenvironment. Five immune cell types within the tumor microenvironment were identified, among which tumor-associated macrophage (TAM) and dendritic cell (DC) were the predominant immune cells. CONCLUSIONS: This transcriptomic analysis revealed distinct cell types and key genes within the tumor microenvironment, offering insights into the cellular heterogeneity and molecular mechanisms of ovarian SCT-NOS, thereby enhancing the understanding and encouraging further investigations into ovarian SCT-NOS.
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Lifespan single-cell transcriptomic atlas of the human prefrontal cortex.
The human brain undergoes profound changes from early development through late adulthood, shaping cognition, behaviour and vulnerability to disease1,2. Understanding how these changes are organized within specific brain regions and cell types is essential for interpreting normal ageing and its relationship to psychiatric and neurodegenerative disorders. The dorsolateral prefrontal cortex has a central role in higher cognitive functions and is particularly sensitive to age-related decline3, yet its cellular and molecular programs across the human lifespan remain poorly defined. Most existing studies4-7 have focused on restricted age ranges or disease-affected brains, limiting the ability to distinguish normative developmental and ageing trajectories from pathological processes. Consequently, a comprehensive, lifespan-resolved reference of cellular states in the human prefrontal cortex has been lacking. Here, using a single-nucleus transcriptomic atlas spanning the human lifespan, we show that the dorsolateral prefrontal cortex exhibits non-linear, cell-type-specific transcriptional trajectories characterized by dynamic remodelling during development, relative stability in midlife and selective molecular reactivation in late adulthood. We identify distinct neuronal and glial programs, including early-life neuronal resilience pathways and late-life glial programs associated with immune activation, stress responses and circadian reorganization. These programs are anatomically organized across cortical layers and grey-white matter domains, revealing coordinated spatial and molecular changes. Together, these findings provide a framework for understanding how cellular programs transition from resilience to vulnerability in the human cortex and establish a foundation for interpreting age-related cognitive decline and disease risk.
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A scATAC-seq atlas of chromatin accessibility in axolotl brain regions.
Axolotl (Ambystoma mexicanum) is an excellent model for investigating regeneration, the interaction between regenerative and developmental processes, comparative genomics, and evolution. The brain, which serves as the material basis of consciousness, learning, memory, and behavior, is the most complex and advanced organ in axolotl. The modulation of transcription factors is a crucial aspect in determining the function of diverse regions within the brain. There is, however, no comprehensive understanding of the gene regulatory network of axolotl brain regions. Here, we utilized single-cell ATAC sequencing to generate the chromatin accessibility landscapes of 81,199 cells from the olfactory bulb, telencephalon, diencephalon and mesencephalon, hypothalamus and pituitary, and the rhombencephalon. Based on these data, we identified key transcription factors specific to distinct cell types and compared cell type functions across brain regions. Our results provide a foundation for comprehensive analysis of gene regulatory programs, which are valuable for future studies of axolotl brain development, regeneration, and evolution, as well as on the mechanisms underlying cell-type diversity in vertebrate brains.
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RNA Metabolism Genes as Prognostic Biomarkers and Therapeutic Targets in Colorectal Cancer Based on the Analysis of Single-Cell and Bulk-RNA Sequencing Data.
Colorectal cancer (CRC) is one of the most common malignancies worldwide and remains a major cause of cancer-related mortality. Increasing evidence suggests that aberrant RNA metabolism contributes to tumour initiation, progression and therapeutic resistance. In this study, we integrated single-cell RNA sequencing and bulk transcriptomic data to identify RNA metabolism-related genes (RMRGs) associated with CRC progression and evaluate their clinical significance. Through comprehensive bioinformatics analyses, 39 differentially expressed RMRGs were identified, with high RMRG activity predominantly enriched in epithelial cell populations. Cell-cell communication analysis revealed enhanced interactions between epithelial cells and other cell types within the tumour microenvironment. Further integration of single-cell and bulk RNA-sequencing datasets identified PCBP3 and NGRN as key prognostic genes. A two-gene prognostic model based on PCBP3 and NGRN was established and validated in independent cohorts, demonstrating favourable predictive performance. Human Protein Atlas data further confirmed the expression of both proteins in colorectal cancer tissues. Immune infiltration analyses indicated that PCBP3 and NGRN were associated with distinct immune-cell infiltration patterns and immunotherapy-related immune status. Functional experiments demonstrated that silencing PCBP3 or NGRN significantly inhibited the proliferation and invasion of HCT116 colorectal cancer cells. Moreover, Western blot analysis suggested that these effects may be mediated, at least in part, through regulation of the PI3K/AKT signalling pathway. Collectively, our findings identify PCBP3 and NGRN as promising prognostic biomarkers and potential therapeutic targets in colorectal cancer and provide new insights into the role of RNA metabolism in colorectal cancer progression and tumour immune regulation.
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Integrating scRNA-seq to explore offspring neurodevelopmental toxicity induced by Cyfluthrin exposure during pregnancy: A fate decision for NSCs.
Cyfluthrin is a widely used insecticide, and studies have shown that its exposure during pregnancy is associated with neurobehavioral abnormalities in offspring, but the mechanism of toxicity is unknown. In this study, we observed the neurodevelopmental toxicity of Cyfluthrin in rat offspring of different ages due to pregnancy exposure, which manifested a series of impairments such as persistent cognitive impairment, neuronal loss in hippocampal tissues, synaptic damage, and altered expression of neurodevelopmental-related factors. Hippocampal scRNA-seq in neonatal rats showed specific cellular responses to prenatal Cyfluthrin exposure. Through DEG intergroup difference analysis, intercellular communication analysis, and mimetic timing analysis, we found that the change in the fate of neural stem cells - alterations in differentiation direction, proliferation, and apoptosis levels - was the main cause of the offspring's developmental toxicity induced by prenatal Cyfluthrin exposure. This inference was verified by our in - vivo and ex - vivo experiments. Our study first constructed a single - cell atlas of the offspring's brain hippocampus exposed to Cyfluthrin during pregnancy. It warns about pesticide intake during pregnancy and nursing in women and provides a theoretical basis for neurodevelopmental toxicity from early - life exposure to environmental pollutants.
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Disease-stage-specific immunometabolic remodeling in pediatric obstructive sleep apnea: a single-cell transcriptomic atlas of adenoid tissue.
Hypertrophied adenoids in children can impair breathing and lead to obstructive sleep apnea (OSA), often accompanied by abnormal growth and weakened stamina and immunity. However, the cause of the pathological transformation in these originally immune-enhancing lymphoid tissues remains unclear. Our study provides the first single cell transcriptomic and immune repertoire atlas of adenoids from normal snoring to mild, moderate, and severe OSA, and identified markedly asynchronous functional modules, transcriptional regulatory networks and intercellular communications during the progression of OSA. Children with severe OSA exhibited exhibit active Hippo, Notch, and Wnt signaling, alongside significant downregulation of energy synthesis. Analysis revealed compromised T-cell and B-cell immunity, as well as reduced antigen processing by innate immune cells, coupled with diminished cell-cell communication in severe OSA group. T-cell receptor and B-cell receptor sequencing results also support more infection imprints and abnormal germinal centers and antibody class switching. Mechanistically, HIF1A-mediated hypoxic signaling likely drives the downregulation of key immune components (including HLA and interferon molecules), positioning it as a promising therapeutic target for OSA.