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GAPDH: unveiling its impact as a key hypoxia-related player in head and neck squamous cell carcinoma tumor progression, prognosis, and therapeutic potential.
Head and neck squamous cell carcinoma (HNSCC), characterized by hypoxia patterns, ranks as the sixth most prevalent malignant tumor worldwide. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays a role in oncogenesis under hypoxic conditions in various cancers. However, its precise function in HNSCC, especially under varied hypoxic conditions, including at high altitudes, remains unclear. Elevated GAPDH mRNA and protein levels in HNSCC relative to normal tissues have been demonstrated through data from The Cancer Genome Atlas (TCGA), GSE29330, and the Human Protein Atlas (P<0.05). This elevation was further confirmed through in vitro experiments utilizing two HNSCC cell lines and a normal oral mucosal epithelial cell line. Additionally, data from TCGA and GSE41613 reveal a correlation between elevated GAPDH expression and diminished overall and progression-free survival in patients (P<0.05). Subsequent analysis identifies GAPDH as an independent risk factor for HNSCC (P<0.05). Using the ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) algorithms, high GAPDH expression was found to be associated with reduced immune scores and diminished anti-tumor cell infiltration, such as CD8+ T cells, in TCGA and GSE41613 datasets (P<0.05). Analysis of single-cell RNA sequencing data from GSE139324 suggests that elevated GAPDH expression hinders communication between plasmacytoid dendritic cells and mast cells (P<0.05). Furthermore, in the TCGA and GSE41613 datasets, GAPDH's biological function is closely tied to hypoxia through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Variation Analysis (GSVA) analyses. Moreover, its expression is linked to one cuproptosis-related gene, five N6-methyladenosine-related genes, six immune checkpoint genes, and pivotal pathways such as MYC and E2F (P<0.05). GAPDH showed excellent predictive value in estimating the efficacy of immunotherapy and 11 anti-tumor drugs (e.g., cisplatin) (P<0.05), using TIDE and pRRophetic algorithms on the TCGA and GSE41613 datasets. Under 1% O2 in vitro, HNSCC cells show elevated GAPDH expression, leading to decreased apoptosis and increased migration, clonogenicity, invasiveness, and resistance to cisplatin (P<0.05). At 5% O2, these effects persisted, albeit less pronouncedly. Inhibiting GAPDH reversed these effects under all oxygen concentrations (P<0.05). Overall, our findings reveal GAPDH as a key hypoxia-related player influencing tumor progression, prognosis, and therapeutic potential in HNSCC.
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A unified cell atlas of vascular plants reveals cell-type foundational genes and accelerates gene discovery.
The pace of gene discovery in plants has slowed as forward genetic screens reach saturation. To address this, we built a unified single-cell atlas of shoot apices from six vascular plant species spanning major evolutionary groups. This cross-species resource allowed us to identify a core set of cell-type foundational genes linked to key tissues such as the epidermis, xylem, and phloem, streamlining gene discovery with greater accuracy. Among these, we uncovered a previously unrecognized clade of X8 domain proteins and JULGI-LIKE as regulators of phloem development. We also identified companion-cell-like cells in ferns and gymnosperms that cannot be distinguished by conventional histological methods and developed an automated cell-type annotation tool for vascular plant cell types, expanding the utility of our approach. Our findings establish a high-resolution framework for identifying key regulators of plant cell types and set an innovative paradigm for studying plant cell-type evolution.
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An atlas of transcriptionally defined cell populations in the rat ventral tegmental area.
The ventral tegmental area (VTA) is a complex brain region that is essential for reward function and frequently implicated in neuropsychiatric disease. While decades of research on VTA function have focused on dopamine neurons, recent evidence has identified critical roles for GABAergic and glutamatergic neurons in reward processes. Additionally, although subsets of VTA neurons express genes involved in the synthesis and transport of multiple neurotransmitters, characterization of these combinatorial populations has largely relied on low-throughput methods. To comprehensively define the molecular architecture of the VTA, we performed single-nucleus RNA sequencing on 21,600 cells from the rat VTA. Analysis of neuronal subclusters identifies selective markers for dopamine and combinatorial neurons, reveals expression profiles for receptors targeted by drugs of abuse, and demonstrates population-specific enrichment of gene sets linked to brain disorders. These results highlight the heterogeneity of the VTA and provide a resource for further exploration of VTA gene expression.
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Using Single-Cell and Spatial Transcriptomes to Understand Stem Cell Lineage Specification During Early Embryo Development.
Embryonic development and stem cell differentiation provide a paradigm to understand the molecular regulation of coordinated cell fate determination and the architecture of tissue patterning. Emerging technologies such as single-cell RNA sequencing and spatial transcriptomics are opening new avenues to dissect cell organization, the divergence of morphological and molecular properties, and lineage allocation. Rapid advances in experimental and computational tools have enabled researchers to make many discoveries and revisit old hypotheses. In this review, we describe the use of single-cell RNA sequencing in studies of molecular trajectories and gene regulation networks for stem cell lineages, while highlighting the integratedexperimental and computational analysis of single-cell and spatial transcriptomes in the molecular annotation of tissue lineages and development during postimplantation gastrulation.
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Effect of immune-related intratumoral microbiota and host gene expression on cancer prognosis.
UNLABELLED: The intratumoral microbiota has been identified as an indispensable part of the tumor microenvironment (TME). However, the relationship between the intratumoral microbiota and host gene expression, as well as its impact on prognosis and TME immunity, remains unclear. We utilized a machine learning-based framework to identify microbiota-host gene associations across 14 tumors from The Cancer Genome Atlas (TCGA) and validated them in 11 tumors from the Gene Expression Omnibus. By calculating immune scores and identifying immune-related microbiota, we developed both a pan-cancer Immune and Prognosis-Related Microbial Score (IPRMS) and cancer-specific IPRMSs and analyzed the relationship between the cancer-specific IPRMSs and immune infiltration at bulk level and single-cell level. Furthermore, we systematically analyzed the potential mechanisms in which the intratumoral microbiota might affect prognosis using survival mediation analyses (SMAs). We identified gene subsets associated with microbiota, which were predominantly enriched in immune-related and cell signaling regulation pathways. Subsequently, we constructed the overall survival-related IPRMS and found that high-IPRMS patients had poorer prognosis in pan-cancer and increased presence of macrophage and cancer-associated fibroblasts. In contrast, low-IPRMS patients showed enrichment in tumor-infiltrating lymphocytes. SMAs suggest that intratumoral microbiota may influence prognosis by affecting immune cells, pathways, and host genes. High-IPRMSs were consistently associated with poorer prognosis and lower abundance of tumor-infiltrating lymphocytes. At the single-cell level, cancer-associated fibroblasts were predominantly enriched in the high-IPRMS group, while tumor-infiltrating lymphocytes were also mainly enriched in the low-IPRMS group. Our research indicates that the intratumoral microbiota was associated with immune and prognosis, which may impact the cancer prognosis by modifying immune cells, pathways, and host gene expression. IMPORTANCE: The intratumoral microbiota is a vital part of the tumor microenvironment, yet its interplay with host gene expression and immune regulation remains unclear. Based on a machine learning framework for the interaction analysis of intratumoral microbiota and host genes, as well as the construction of the Immune and Prognosis-Related Microbial Score, our findings suggest that intratumoral microbiota may influence gene expression by affecting host pathways, especially immune-related pathways. Moreover, immune-related intratumoral microbiota are significantly associated with patient survival and TME immunity and may influence prognosis by affecting immune cells, pathways, or gene expression, offering new perspectives and potential biomarkers for predicting personalized patient prognosis in the future.
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CDH6 as a prognostic indicator and marker for chemotherapy in gliomas.
Glioma is the most malignant cancer of the central nervous system. There are various therapies for treating gliomas, but their outcomes are not satisfactory. Therefore, new targets for glioma treatment are needed. This study examined the cadherin-6 (CDH6) expression in gliomas using The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets. CDH6 expression positively correlated with the World Health Organization (WHO) tumor grade and negatively correlated with patient prognosis. A significant decrease in CDH6 promoter methylation was identified with an increase in the WHO grade severity. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that CDH6 might be involved in cell-cell interactions and immune processes in the glioma microenvironment. Weighted gene co-expression network analysis revealed a correlation between CDH6 and cell adhesion molecules, focal adhesions, phosphatidylinositol 3-kinase-protein kinase B signaling pathways, nuclear division, chromosome segregation, mitotic nuclear division, and immune-related pathways. CDH6 strongly correlated with immunosuppressive cells, including regulatory T cells, monocytes, macrophages, tumor-associated macrophages, and myeloid-derived suppressor cells. It also showed correlations with immune-active cells such as B cells, CD8+ T cells, and dendritic cells. Single-cell analysis showed that CDH6 was expressed mainly in astrocyte (AC)-like malignant cells. Differentially expressed genes of AC-like malignant cells were found to be associated with stress response, membranous processes, viral infections, and several types of cancers. Potential drugs associated with high CDH6 expression were also predicted, including AMG-22, rutin, CCT128930, deforolimus, bis(maltolato)oxovanadium, anagrelide, vemurafenib, CHIR-98014, and AZD5582. Thus, this study showed that CDH6 correlates with glioma immune infiltration, it is expressed mainly in AC-like malignant cells, and it may act as a new target for glioma therapy.
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Multi-species meta-analysis identifies transcriptional signatures associated with cardiac endothelial responses in the ischaemic heart.
AIM: Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration. METHODS AND RESULTS: We carried out a comprehensive meta-analysis of integrated single-cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularization. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1, and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularization. CONCLUSION: We present a high-resolution single-cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development.
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A single-cell atlas of multiple myeloma defines malignant archetypes and proliferative states.
Multiple myeloma (MM) is a plasma-cell malignancy with extensive genomic and transcriptional heterogeneity, limiting disease classification and precision therapy. Here we generated a clinically annotated, population-scale, single-cell atlas of MM from 341 individuals spanning the disease and treatment continuum. We identified five recurrent malignant transcriptional archetypes and an orthogonal proliferative program associated with genomic features, therapeutic resistance and clinical outcomes. Validation in the independent CoMMpass cohort demonstrated robustness, prognostic relevance and portability across platforms. We developed a single-cell, target-discovery pipeline prioritizing malignant enrichment, cell-type specificity and tissue restriction, identifying FCRL2 as a plasma-restricted or B cell-lineage-restricted surface target expressed by malignant plasma cells. FCRL2-targeted chimeric antigen receptor T cells demonstrated antigen-specific activity in vitro and survival benefit in vivo. Together, these data provide a clinically actionable blueprint for patient stratification and precision target nomination in plasma-cell malignancies.
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Identification and validation of a novel signature based on immune‑related genes from epithelial cells to predict prognosis and treatment response in patients with lung squamous cell cancer by integrated analysis of single‑cell and bulk RNA sequencing.
Epithelial cells are associated with tumor immunity through interstitial transformation, yet the role of epithelial immune-related genes (EIGs) in this process remains unclear. Comprehending the mechanisms behind EIGs within lung squamous cell carcinoma (LUSC) may offer an explanation to these issues. The present study aimed to explore the biological role of EIGs in patients with LUSC. Based on data from the Gene Expression Omnibus and The Cancer Genome Atlas databases, a survival model and nomogram was established. This model and nomogram were used to study the mechanism of EIGs in LUSC and its medical significance by enrichment analysis, tumor microenvironment, immune cell infiltration and immune function correlation analysis. Finally, reverse transcription-quantitative PCR (RT-qPCR) and external dataset were used to assess the expression of the EIGs. The survival model was used to develop 4 EIGs as predictors for patient outcomes. Survival curves revealed that higher risk patients had more negative outcomes. This model and the nomogram developed based entirely on this model had an accurate prognosis predictive LUSC. The enrichment analysis indicated that pathways related to antigen processing and presentation, as well as Epstein-Barr virus infection, were prevalent in the high-risk populations. The research on immune infiltration demonstrated a notable rise in activated dendritic cells and neutrophils in the high-risk group. Furthermore, the results revealed that the high-risk populations are particularly susceptible to the effects of afureserpine, gefitinib and savolitinib. Finally, the outcomes of RT-qPCR were consistent with those of the bioinformatics analysis. In conclusion, the risk evaluation model and nomogram are effective in forecasting the prognosis and guiding drug selection for patients with LUSC. A worse prognosis in patients with high risk may be associated with certain viral infections and antigen processing and presentation.
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A Transcriptomic Atlas of Healthy Human Skin Links Regional Identity to Inflammatory Disease.
Human skin is not a uniform organ but a mosaic of anatomically distinct niches, with each site finely tuned to unique environmental demands and immune pressures. Yet, the molecular determinants that define these regional identities and their relationship to site-specific vulnerability to inflammatory disease remain poorly understood. Here, we generate a high-resolution single-cell atlas of human skin, profiling 274,834 cells from 96 healthy samples across 7 anatomically distinct sites (acral, arm, axilla, back, face, leg and scalp). Our analysis reveals striking region-specific transcriptional and cellular networks, uncovering how local immune-stromal crosstalk governs tissue homeostasis and underpins anatomical susceptibility to distinct inflammatory diseases such as such as systemic lupus erythematosus (SLE), atopic dermatitis (AD), and psoriasis. These findings illuminate the tissue-intrinsic foundations of regional immune identity and provide a blueprint/resource for the development of precision therapies tailored to the distinct immunological microenvironments of specific anatomical skin sites.