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Cellular dynamics in tumour microenvironment along with lung cancer progression underscore spatial and evolutionary heterogeneity of neutrophil.
BACKGROUND: The cellular dynamics in the tumour microenvironment (TME) along with non-small cell lung cancer (NSCLC) progression remain unclear. METHODS: Multiplex immunofluorescence test detecting 10 immune-related markers on 553 primary tumour (PT) samples of NSCLC was conducted and spatial information in TME was assessed by the StarDist depth learning model. The single-cell transcriptomic atlas of PT (n = 4) and paired tumour-draining lymph nodes (TDLNs) (n = 5 for tumour-invaded, n = 3 for tumour-free) microenvironment was profiled. Various bioinformatics analyses based on Gene Expression Omnibus, TCGA and Array-Express databases were also used to validate the discoveries. RESULTS: Spatial distances of CD4+ T cells-CD38+ T cells, CD4+ T cells-neutrophils and CD38+ T cells-neutrophils prolonged and they were replaced by CD163+ macrophages in PT along with tumour progression. Neutrophils showed unique stage and location-dependent prognostic effects. A high abundance of stromal neutrophils improved disease-free survival in the early-stage, whereas high intratumoural neutrophil infiltrates predicted poor prognosis in the mid-to-late-stage. Significant molecular and functional reprogramming in PT and TDLN microenvironments was observed. Diverse interaction networks mediated by neutrophils were found between positive and negative TDLNs. Five phenotypically and functionally heterogeneous subtypes of tumour-associated neutrophil (TAN) were further identified by pseudotime analysis, including TAN-0 with antigen-presenting function, TAN-1 with strong expression of interferon (IFN)-stimulated genes, the pro-tumour TAN-2 subcluster, the classical subset (TAN-3) and the pro-inflammatory subtype (TAN-4). Loss of IFN-stimulated signature and growing angiogenesis activity were discovered along the transitional trajectory. Eventually, a robust six neutrophil differentiation relevant genes-based model was established, showing that low-risk patients had longer overall survival time and may respond better to immunotherapy. CONCLUSIONS: The cellular composition, spatial location, molecular and functional changes in PT and TDLN microenvironments along with NSCLC progression were deciphered, highlighting the immunoregulatory roles and evolutionary heterogeneity of TANs.
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Spatiotemporal dynamics of neuron differentiation and migration in the developing human spinal cord.
Precise formation of complex neural circuits in the spinal cord, achieved through the integration of diverse neuronal populations, is essential for central nervous system function. However, the specialization and migration of human spinal cord neurons remain poorly understood. In this study, we perform single-cell transcriptome sequencing of human spinal cord from Carnegie Stages (CS) 16-21 and mouse spinal cord from embryonic day (E) 8.0-11.5, complemented by in situ sequencing of human spinal cord (CS 16-20). Our results reveal the critical role of the precursor state in neuronal differentiation and migration, identifying key transcription factors that regulate these processes across species. Notably, each neuronal lineage expresses unique markers as early as the progenitor stage at the spinal cord midline, and subsequently undergoes a shared transcriptional program during precursor commitment that guides migration. This synchronized migration, validated by spatial transcriptomics, occurs in both dorsal and ventral regions. Our findings offer important insights into the migration patterns and regulatory factors that guide spinal cord neuron subtype specification during embryogenesis.
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Construction and validation of a lipid metabolism-related genes prognostic signature for skin cutaneous melanoma.
BACKGROUND: Skin cutaneous melanoma (SKCM) is a highly aggressive form of skin cancer, characterized by a poor prognosis, particularly in advanced stages. Emerging evidence has underscored the pivotal role of lipid metabolism in cancer progression, influencing tumor growth, metastasis, and therapeutic resistance. However, the potential of lipid metabolism-related genes (LMGs) as prognostic biomarkers in SKCM remains largely unexplored. This study aims to investigate the functional roles and prognostic significance of LMGs in patients with SKCM. METHODS: A total of 776 LMGs were obtained from the Molecular Signature Database (MSigDB). mRNA sequencing data and corresponding clinical follow-up information for SKCM were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Based on LMGs expression profiles, the non-negative matrix factorization (NMF) algorithm was applied to identify distinct molecular subtypes. Subsequently, weighted correlation network analysis (WGCNA) was performed to detect co-expressed gene modules associated with these subtypes. To construct a prognostic risk model, least absolute shrinkage and selection operator (LASSO) regression and Cox regression analyses were conducted. The resulting prognostic signature was validated across multiple external cohorts (GSE65904 and GSE54467). Further analyses were carried out to compare immune cell infiltration levels, expression of immune checkpoint-related genes, and predicted immunotherapy responses between different risk groups. A nomogram integrating clinical factors and risk scores was developed to predict survival outcomes and assess the prognostic risk for SKCM patients. Additionally, genome mutation profiling and pan-cancer analyses based on the prognostic signature were performed to investigate its broader oncological relevance. The expression patterns of LMGs within the SKCM tumor microenvironment were further explored using single-cell RNA sequencing data from the GSE72056 dataset. Finally, functional validation of the most critical hub gene was conducted through both in vitro and in vivo experiments. RESULTS: A 10 LMGs prognostic signature was successfully established and validated to predict survival outcomes in SKCM patients, serving as an independent prognostic factor for overall survival. This signature was significantly associated with immune cell infiltration, with the low-risk group exhibiting a higher abundance of antitumor immune cells compared to the high-risk group. Additionally, the low-risk group demonstrated elevated expression levels of key immune checkpoint genes, including PD-1, PD-L1, CTLA-4, and LAG3, along with higher Immunophenoscore (IPS), suggesting a more favorable immune microenvironment and potentially better responsiveness to immunotherapy. Moreover, functional studies further revealed that knockdown of CCNA2 inhibited melanoma cell proliferation, migration, and invasion in vitro, while suppressing tumorigenicity in vivo. These findings underscore the potential of CCNA2 as a novel therapeutic target in SKCM. CONCLUSION: In summary, this study successfully established a 10 LMGs prognostic signature for predicting survival outcomes and identified CCNA2 as a promising therapeutic target in SKCM.
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Metabolic alterations driven by LDHA in CD8 + T cells promote immune evasion and therapy resistance in NSCLC.
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Despite advancements in treatment, prognosis for patients with advanced stages remains poor. Metabolic reprogramming in the tumor microenvironment, particularly abnormal glycolysis, plays a crucial role in immune evasion and treatment response. We collected nine single-cell datasets to create a single-cell atlas of CD8 + T cells from 89 NSCLC patients, revealing ten distinct states of these cells. We employed a multimodal data analysis approach, integrating bulk transcriptomics, single-cell transcriptomics, spatial transcriptomics, and proteomics. Using 117 machine learning models, we identified key genes associated with NSCLC metastasis. Notably, the StepCox[forward] + Lasso model was instrumental in pinpointing key genes that significantly impact disease prognosis. Our analysis revealed that LTB + LDHA + CD8 + T cells have a distinct metabolic and immune phenotype, characterized by enhanced glycolysis and elevated lactate production. This not only facilitates tumor cell migration and invasion but also impairs the cytotoxic function of CD8 + T cells. Furthermore, our machine learning models identified four key genes significantly associated with NSCLC metastasis: TBCD, PTPRC, LDHA, and ACTR2. Of these, high LDHA expression was strongly linked to poorer responses to immunotherapy and a higher risk of therapy resistance. LTB + LDHA + CD8 + T cells also reduced antitumor immune responses by inhibiting the secretion of effector molecules like GNLY. Additionally, elevated LDHA expression was associated with reduced CD8 + T cell infiltration, which further promotes tumor immune evasion. This study highlights the heterogeneity of CD8 + T cells in NSCLC, emphasizing the unique role of the LTB + CD8 + Tn subpopulation in metastasis. LDHA is identified as a critical key gene with a significant impact on immunotherapy outcomes, presenting a potential therapeutic target. These insights offer new biomarkers and targeted strategies for personalized immune therapy.
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NR3C2 affects the proliferation and invasiveness of colon cancer cells through the Wnt/β-Catenin signaling pathway.
PURPOSE: The aim of this study was to explore the potential correlation between the nuclear receptor subfamily 3 group C member 2 (NR3C2) and outcomes of colon cancer, along with the mechanisms underlying this association. METHOD: mRNA (messenger RNA) data and clinical records pertaining to colon cancer were retrieved from The Cancer Genome Atlas (TCGA) database. The analysis of NR3C2 expression discrepancies between normal colon and tumor tissues was conducted using R software. In addition, we also studied the relationship between NR3C2 expression and prognosis, pathological parameters. The relative role of NR3C2 were further predicted through bioinformatics methods and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of NR3C2 in colon cancer. Single-cell data from colon cancer samples in the GEO (Gene Expression Omnibus) database further investigated the mechanism of the lower survival associated with NR3C2 dysregulation. NR3C2 expression in three fresh colon cancer samples and their respective paracancer samples was determined. Furthermore, colon cancer cell models overexpressing NR3C2 and with knockdown NR3C2 were constructed by lentiviral vector transfection. Cell Counting Kit-8 assay, transplantation of tumors in nude mice and transwell assays were used to examine the proliferation, migration and invasion of colon cancer cells. The effect on the Wnt/β-catenin pathway, activities of cellular autophagy and cell apoptosis were examined by assessing the expression levels of several key proteins, including Bcl-2, Bax, and LC3. RESULTS: We found that NR3C2 was found a significantly lower level in colon cancer tissues than in adjacent tissues, which was associated with distant and lymphatic metastases, clinical stage, and poor clinical outcome, and it was an independent prognostic factor and potential marker of colon cancer. Single-cell transcriptome data identified the subset of circulating T and B cells with high expression of NR3C2, which is involved in TNF signaling pathway. Functional experiments show that downregulation of NR3C2 resultsed in the activation of the Wnt/β-catenin signaling pathway, and promotesd the proliferation and invasion of colon cancer cells while suppressing cell autophagy and apoptosis. CONCLUSION: NR3C2 may regulate Wnt/β-catenin to affect the proliferation, invasion apoptosis and autophagy of colon cancer, and this axis is a potential target for the treatment of colon cancer.
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Cytoskeletal protein SPTA1 mediating the decrease in erectile function induced by high-fat diet via Hippo signaling pathway.
BACKGROUND: The mechanism of high-fat diet (HFD)-induced decrease in erectile function has not been elucidated, and in previous studies, spectrin alpha, erythrocytic 1 (SPTA1) is a cytoskeletal protein that regulates cellular function, which belongs to a family of proteins that can affect cell and tissue growth and development by regulating YAP, an effector on the Hippo signaling pathway, but its particular role has not been elucidated. OBJECTIVE: To explore the role of SPTA1 in the abnormality of erectile function induced by HFD. METHODS: We analyzed the penile tissues of mice on normal diet and HFD by transcriptomics and screened for differentially expressed genes, further identified closely related target genes in rat penile tissues, and verified target gene expression in in vitro construction of high-glucose (HG)-treated corpus cavernosum endothelial cells (CCECs) and corpus cavernosum smooth muscle cells (CCSMCs) models. The distribution of target genes in various cell populations in penile tissues was retrieved by single-cell sequencing Male Health Atlas database. Moreover, interfering with target genes was further applied to explore the mechanisms involved in erectile function decline. RESULTS: Transcriptomic analysis screened out down-regulated differential gene SPTA1; Western blot and immunohistochemistry results showed that SPTA1 expression significantly decreased in the penile tissues of Sprague-Dawley (SD) rats in the HFD group. Immunofluorescence staining showed a positive expression of CD31 and VWF in CCECs and a positive expression of α-SMA in CCSMCs. The expression level of SPTA1 protein significantly decreased in the HG group of CCECs and CCSMCs. The expression of SPTA1 mRNA significantly decreased in CCSMCs while significantly increased in CCECs. SPTA1 may have various expression patterns and biological functions in different cell populations. Real-time quantitative PCR results showed that the siSPTA1 transfected in CCSMCs had a significant interference effect compared with the control siNC. Transfection of siSPTA1 into CCSMCs resulted in the significant down-regulation of mRNA and protein expression of eNOS, and significant up-regulation of YAP, Caspase-1, GSDMD, GSDMD-N IL-18, and IL-1β protein expression levels. The expression level of CCSMCs contractile-type protein α-SMA was significantly down-regulated. CONCLUSIONS: The down-regulation of SPTA1 in SD rats fed with HFD may induce cell pyroptosis and lead to the decrease of erectile function by activating the Hippo pathway; these findings may provide new therapeutic targets for improving erectile function.
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Single-cell and tissue transcriptomes unveil factors regulating vein initiation and development in grass leaf primordia.
Compared to the C3 plant rice (Oryza sativa), veins in the leaves of the C4 plant maize (Zea mays) are more densely arranged, but the mechanisms controlling vein initiation and differentiation remain unclear. This study systematically investigated the developmental patterning of vein formation in leaf primordia of maize and rice. Single-nucleus transcriptomic atlas of maize primordia revealed distinct middle ground tissue and procambium cell populations and a role for auxin in vein initiation inferred. Pseudo-time trajectory analysis further facilitated the identification of marker genes in ground tissue and procambial cell types including ETHYLENE-RESPONSIVE ELEMENT BINDING 114 (ZmEREB114), AUXIN IMPORT CARRIER 3 (ZmAIC3), ZmEREB161, and AUXIN AMIDO SYNTHETASE 2 (ZmAAS2). An experimental system was established in which the interplay between SHORT-ROOT1 (ZmSHR1) and auxin was used to suppress or restore vein formation in rice leaf primordia. Notably, expression of the rice genes GRETCHEN HAGEN 3.8 (OsGH3.8, homologous to ZmAAS2) and AUXIN RESISTANT 1 (OsAUX1, homologous to ZmAIC3) was suppressed by ZmSHR1 but promoted by auxin. Collectively this study provides single-cell resolved resources for early stages of grass leaf development, an experimental system for manipulating vein initiation in rice, and a model about how the interplay between SHR function and auxin response regulates vein patterning in maize and rice leaves.
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A New Ferroptosis-Related lncRNA Signature Predicts the Prognosis of Bladder Cancer Patients.
Background: Ferroptosis is closely related to the occurrence and development of cancer. An increasing number of studies have induced ferroptosis as a treatment strategy for cancer. However, the predictive value of ferroptosis-related lncRNAs in bladder cancer (BC) still need to be further elucidated. The purpose of this study was to construct a predictive signature based on ferroptosis-related long noncoding RNAs (lncRNAs) to predict the prognosis of BC patients. Methods: We downloaded RNA-seq data and the corresponding clinical and prognostic data from The Cancer Genome Atlas (TCGA) database and performed univariate and multivariate Cox regression analyses to obtain ferroptosis-related lncRNAs to construct a predictive signature. The Kaplan-Meier method was used to analyze the overall survival (OS) rate of the high-risk and low-risk groups. Gene set enrichment analysis (GSEA) was performed to explore the functional differences between the high- and low-risk groups. Single-sample gene set enrichment analysis (ssGSEA) was used to explore the relationship between the predictive signature and immune status. Finally, the correlation between the predictive signature and the treatment response of BC patients was analyzed. Results: We constructed a signature composed of nine ferroptosis-related lncRNAs (AL031775.1, AL162586.1, AC034236.2, LINC01004, OCIAD1-AS1, AL136084.3, AP003352.1, Z84484.1, AC022150.2). Compared with the low-risk group, the high-risk group had a worse prognosis. The ferroptosis-related lncRNA signature could independently predict the prognosis of patients with BC. Compared with clinicopathological variables, the ferroptosis-related lncRNA signature has a higher diagnostic efficiency, and the area under the receiver operating characteristic curve was 0.707. When patients were stratified according to different clinicopathological variables, the OS of patients in the high-risk group was shorter than that of those in the low-risk group. GSEA showed that tumor- and immune-related pathways were mainly enriched in the high-risk group. ssGSEA showed that the predictive signature was significantly related to the immune status of BC patients. High-risk patients were more sensitive to anti-PD-1/L1 immunotherapy and the conventional chemotherapy drugs sunitinib, paclitaxel, cisplatin, and docetaxel. Conclusion: The predictive signature can independently predict the prognosis of BC patients, provides a basis for the mechanism of ferroptosis-related lncRNAs in BC and provides clinical treatment guidance for patients with BC.
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The Expression of the LDLR, LDLRAP1, and PCSK9 Genes has Prognostic Significance in Triple-negative Breast Cancer.
AIMS: The purpose of this study was to investigate the prognostic significance of cholesterol uptake genes in predicting the survival of breast cancer patients. BACKGROUND: Cholesterol plays a crucial role in the homeostasis of tumor cells. It is known that cholesterol levels can influence important parameters of the disease, such as sensitivity to therapy, progression, and metastasis of cancer. Previous studies suggest that breast cancer subtypes exhibit differences in metabolism. OBJECTIVE: The objectives of this study were to determine whether cholesterol uptake genes have prognostic significance for overall survival in breast cancer patients, evaluate if this prognostic significance varies between breast cancer subtypes, and identify differences in the expression of cholesterol uptake genes among these subtypes. METHODS: Data from mRNA sequencing of tumors from the Cancer Genome Atlas (TCGA) portal were analyzed. Tumors were classified into molecular subtypes, and the prognostic significance of cholesterol uptake gene expression levels was evaluated for each subtype. DESeq2 and Fisher's test were used to assess differences in gene expression. RESULTS: High expression levels of genes involved in de novo cholesterol synthesis were associated with poor prognosis for the Basal-like and Luminal A breast cancer subtypes. The prognostic significance of low-density lipoprotein receptor (LDLR), LDLR adapter protein 1 (LDLRAP1), and proprotein convertase subtilisin/kexin type 9 (PCSK9), which are responsible for exogenous cholesterol uptake, varied across subtypes. Specifically, low expression of LDLR was associated with a favorable prognosis for the luminal A (OR = 2.17; FDR = 0.0048) and luminal B (OR = 2.21; FDR = 0.015) subtypes but indicated poor prognosis in the basal-like subtype (OR = 0.48; FDR = 0.05). No genes were significant for prognosis prediction in the HER2-positive subtype. The HER2+ subtype exhibited higher expression of cholesterol uptake genes compared to the basal-like subtype based on the analysis of tumor mRNA sequencing (OR = 6.45, p-value = 3.07E-05). This finding was also confirmed through the study of publicly available single-cell sequencing data (OR = 40.3, p-value = 2.19e-07), which may contribute to the differences in their prognostic significance. CONCLUSION: The prognostic significance of cholesterol uptake gene expression varies among breast cancer subtypes. Precise fitting of biomarkers into breast cancer subtypes may aid in more accurate patient stratification and improve treatment approaches.
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Single-cell eQTL Mapping Reveals Cell Subtype-specific Genetic Control and Mechanism in Malignant Transformation of Colorectal Cancer.
UNLABELLED: Colorectal cancer is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. In this study, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular cross-talk during colorectal cancer development. Additionally, we created a colorectal cancer single-cell expression quantitative trait locus (sc-eQTL) map identifying 16,833 significant pairs across 28 cell subtypes, with more than 76% of sc-eQTLs being cell type-specific and fewer than 15% detectable in bulk datasets. A polygenic risk score derived from sc-eQTLs substantially improved colorectal cancer risk prediction. We prioritized rs4794979 that is associated with an increased colorectal cancer risk (OR = 1.11, P = 2.04 × 10-12) by promoting LGALS9 expression mediated by ELK1. Elevated LGALS9 in epithelia interacts with SLC1A5 on fibroblasts, promoting transformation into cancer-associated fibroblasts and simultaneously inducing CD8+ T-cell exhaustion via the LGALS9-TIM3 axis, thereby facilitating colorectal cancer development. Blocking the LGALS9-TIM3 axis enhanced anti-PD-1 therapy to inhibit colorectal cancer progression. SIGNIFICANCE: Our study provides a valuable resource, including a dynamic single-cell landscape and a robust colorectal cancer sc-eQTL atlas, and elucidates the cell type-specific regulation and important cross-talk mechanisms between cell types in the tumor microenvironment, offering deep insights into colorectal cancer tumorigenesis and targeted therapies.