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Targeting Lymphotoxin Beta and Paired Box 5: a potential therapeutic strategy for soft tissue sarcoma metastasis.
BACKGROUND: Soft tissue sarcomas (STS) has a high rate of early metastasis. In this study, we aimed to uncover the potential metastasis mechanisms and related signaling pathways in STS with differentially expressed genes and tumor-infiltrating cells. METHODS: RNA-sequencing (RNA-seq) of 261 STS samples downloaded from the Cancer Genome Atlas (TCGA) database were used to identify metastasis-related differentially expressed immune genes and transcription factors (TFs), whose relationship was constructed by Pearson correlation analysis. Metastasis-related prediction model was established based on the most significant immune genes. CIBERSORT algorithm was performed to identify significant immune cells co-expressed with key immune genes. The GSVA and GSEA were performed to identify prognosis-related KEGG pathways. Ultimately, we used the Pearson correlation analysis to explore the relationship among immune genes, immune cells, and KEGG pathways. Additionally, key genes and regulatory mechanisms were validated by single-cell RNA sequencing and ChIP sequencing data. RESULTS: A total of 204 immune genes and 12 TFs, were identified. The prediction model achieved a satisfactory effectiveness in distant metastasis with the Area Under Curve (AUC) of 0.808. LTB was significantly correlated with PAX5 (P < 0.001, R = 0.829) and hematopoietic cell lineage pathway (P < 0.001, R = 0.375). The transcriptional regulatory pattern between PAX5 and LTB was validated by ChIP sequencing data. CONCLUSIONS: We hypothesized that down-regulated LTB (immune gene) modulated by PAX5 (TF) in STSs may have the capability of inducing cancer cell metastasis in patients with STS.
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An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors.
Analysis of the human hematopoietic progenitor compartment is being transformed by single-cell multimodal approaches. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) enables coupled surface protein and transcriptome profiling, thereby revealing genomic programs underlying progenitor states. To perform CITE-seq systematically on primary human bone marrow cells, we used titrations with 266 CITE-seq antibodies (antibody-derived tags) and machine learning to optimize a panel of 132 antibodies. Multimodal analysis resolved >80 stem, progenitor, immune, stromal and transitional cells defined by distinctive surface markers and transcriptomes. This dataset enables flow cytometry solutions for in silico-predicted cell states and identifies dozens of cell surface markers consistently detected across donors spanning race and sex. Finally, aligning annotations from this atlas, we nominate normal marrow equivalents for acute myeloid leukemia stem cell populations that differ in clinical response. This atlas serves as an advanced digital resource for hematopoietic progenitor analyses in human health and disease.
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RAC2 as a Tumor-Suppressive Biomarker Associated with T Cell Infiltration in Breast Cancer.
Background: RAC2 is critical in regulating the homeostasis of hematopoietic stem cells. Nonetheless, its role in breast cancer (BC) remains unclear, necessitating further investigation. Methods: The expression of RAC2 in BC and healthy tissues was acquired from The Cancer Genome Atlas. Its validity was further assessed using datasets from the gene expression omnibus database. The Tumor Immune Single-cell Hub database was used to collect and analyze the single-cell RNA sequencing datasets of BC. The diagnostic relevance of RAC2 was evaluated using receiver operating characteristic curves. Further assessment was carried out via enrichment analyses; Gene Set Analysis, immune scoring, single-cell sequencing, and immunohistochemical analysis were conducted to confirm the relationship between RAC2 expression and immune infiltration. Results: RAC2 expression was notably heightened in BC (p < 0.001). It was observed that a better prognosis was linked to heightened expression of RAC2 (p < 0.01), with the diagnostic efficacy of the marker noted to be good (area under the curve = 0.858). We found a lower percentage of protumor immune cells and a greater proportion of antitumor immune cells in the high RAC2. Our analysis revealed alterations in gene expression and an enriched network of immune pathways influenced by RAC2. Notably, cytotoxic genes, chemokines, chemokine receptors, immunostimulators, and immunosuppressive molecules positively correlated with RAC2 expression. RAC2 expression reliably predicted how patients would respond to two different therapeutic approaches in BC. Conclusions: The RAC2 was found to be a key biomarker in BC in the current study, demonstrating considerable potential as a prognostic and diagnostic marker. These results highlight the RAC2 potential to improve precision medicine strategies and treatment outcomes for patients with BC.
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Characterization of the tumour microenvironment phenotypes in malignant tissues and pleural effusion from advanced osteoblastic osteosarcoma patients.
PURPOSE: Malignant pleural effusion (MPE) is an adverse prognostic factor in patients with osteoblastic osteosarcoma; however, the cellular contexts of MPE are largely unknown. EXPERIMENTAL DESIGN: We performed single-cell RNA-sequencing (scRNA-seq) on 27 260 cells from seven MPE samples and 91 186 cells from eight osteosarcoma tissues, including one recurrent, one lung metastasis and six primary tumour (PT) samples, to characterize their tumour microenvironment. RESULTS: Thirteen main cell groups were identified in osteosarcoma tumour and MPE samples. Immune cells dominate the cellular contexts in MPE with more T/NK cells and less osteoclasts compared to PT samples. Of T/NK cells, CD8+ GNLY+ , CD8+ KLRC2+ T cells and FCGR3A+ NK cells were enriched in MPE but CD4+ FOXP3+ Tregs were enriched in PT samples. Naïve IGHD+ B and immune regulatory IGHA1+ B cells were largely identified in MPE, whereas bone metabolism-related CLEC11A+ B cells were significantly enriched in osteosarcoma PT. M2-type TAMs, including CLEC11A_TAM, C1QC_TAM and Prolif_TAMs, among myeloid cells were enriched in PT, which may suppress cytotoxicity activities of T cells through multiple ligand-receptor interactions. Mature LAMP3+ DCs were transformed from CD1C+ DC and CLEC9A+ DC sub-clusters when exposure to tumour alloantigens, which may improve T cell cytotoxicity activities on tumour cells under anti-PD-L1 treatments. In further, immune cells from MPE usually present up-regulated glycolysis and down-regulated oxidative phosphorylation and riboflavin metabolism activities compared to those in PT samples. CONCLUSIONS: Our study provided a novel cellular atlas of MPE and PT in patients with advanced osteosarcoma, which may provide potential therapeutic targets in the future.
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Generation of a Litopenaeus vannamei hepatopancreas cell atlas from single nuclei transcriptomics using a new nuclei isolation method.
BACKGROUND: Crustacean aquaculture is one of the most important food sectors globally and projected to grow. It is a source of nutritious and economic animal protein in many countries. As the global demand for sea food increases, and with an increase in climatic and pathogenic threats to the industry, curating our current knowledge about crustaceans, as well as generating new tools and resources to help minimise the impact of various diseases on the sustainability of the industry is of the utmost importance to increase the resilience of the farmed animal stocks. The main aim of this pilot study was to create a new cell atlas for Pacific whiteleg shrimp (Litopenaeus vannamei) hepatopancreas which encapsulates both the different hepatocyte cell states as well as the various supporting cells found throughout the hepatopancreas, while developing a new method for nuclei isolation and data analysis in the species. RESULTS: We developed new protocols for TST-based nuclei isolation which could be used to successfully isolate and process crustacean-derived nuclei for single nuclei RNA-sequencing analysis with minimal nuclei degradation using frozen hepatopancreas tissue from healthy L. vannamei adults. The bioinformatic analysis that followed allowed us to create a new cell atlas for the hepatopancreas which details the different hepatocyte cell states. Additionally, we built up on the existing knowledge by also analysing the multiple supporting cell clusters such as IECs, fibroblasts and myocytes, which helps improve our understanding of the characteristics of this immune-related organ. CONCLUSION: Overall, 4005 cells were assigned to nine different clusters. Distinct marker genes suggest unique functions of each hepatocyte subtypes and adjacent supportive cells. The new TST-based isolation method for frozen or archived nuclei is particularly useful for processing difficult samples, such as the hepatopancreas, minimise stress and dissociation bias while allowing for greater flexibility between tissue sampling and processing times. Combining the knowledge gained through this study with past and future work in other penaeid shrimp species will allow us to create a powerful resource that will help uncover new knowledge about these important species, especially in the field of stress and immunity.
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Integrated analysis of tumor-associated macrophage infiltration and prognosis in ovarian cancer.
Ovarian cancer (OC) is a frequently lethal gynecologic malignancy, characterized by a poor prognosis and high recurrence rate. The immune microenvironment has been implicated in the progression of OC. We characterized the immune landscape in primary and malignant OC ascites using single-cell and bulk transcriptome raw OC data acquired from the Gene Expression Omnibus and The Cancer Genome Atlas databases. We then used the CIBERSORT deconvolution algorithm, weighted gene co-expression network analysis, univariate and multivariate Cox analyses, and the LASSO algorithm to develop a tumor-associated macrophage-related gene (TAMRG) prognostic signature, which enabled us to stratify and predict overall survival (OS) of OC patients. In addition, inter- and intra-patient heterogeneity of infiltrating immune cells was characterized at single-cell resolution. Tumor-infiltrating macrophages with an M2 phenotype exhibited immunosuppressive activity. M1 macrophages positively correlated with OS, whereas activated mast cells, neutrophils, M2 macrophages, and activated memory CD4+ T cells were all negatively correlated with OS. A total of 219 TAMRGs were identified, and a novel 6-gene signature (TAP1, CD163, VSIG4, IGKV4-1, CD3E, and MS4A7) with independent prognostic value was established. These results show that a TAMRG-based signature may be a promising prognostic and therapeutic target in OC.
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Targeting ORMDL2 in glioblastoma through integrated landscape of high-throughput sequencing and pharmacogenomic analysis.
Glioblastoma multiforme (GBM) is characterized by rapid progression, therapeutic resistance, and a profoundly immunosuppressive tumor microenvironment. Emerging evidence suggests that endoplasmic reticulum (ER)-associated macromolecules play critical roles in tumor adaptation. In this study, we performed a multi-omics investigation of orosomucoid-like protein 2 (ORMDL2), a conserved ER membrane protein involved in sphingolipid biosynthesis and ER stress regulation, and uncovered its regulatory functions in GBM progression. Transcriptomic analyses across The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA) revealed elevated ORMDL2 expression in GBM tissues which causes poor prognosis. The MetaCore pathway and Gene Set Enrichment Analysis (GSEA) identified ORMDL2's involvement in antigen presentation via a major histocompatibility complex I (MHC class I), unfolded protein response (UPR), and mitochondrial apoptotic signaling. Single-cell RNA-sequencing data and the Human Protein Atlas showed ORMDL2 enrichment in tumor stromal cells. Pharmacogenomic correlation via the Genomics in Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) database suggested that ORMDL2 expression was associated with resistance to DNA damage response inhibitors such as etoposide, doxorubicin, talazoparib, and might interact with sphingolipid-targeting compounds. Collectively, our findings establish ORMDL2 as a multi-functional macromolecular regulator of immune suppression and therapeutic resistance in GBM, providing new mechanistic insights and potential targets for translational medicines.
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The prognostic biomarker TPGS2 is correlated with immune infiltrates in pan-cancer: a bioinformatics analysis.
BACKGROUND: Tubulin polyglutamylase complex subunit 2 (TPGS2) is an element of the neuronal polyglutamylase complex that plays a role in the post-translational addition of glutamate residues to C-terminal tubulin tails. Recent research has shown that TPGS2 is associated with some tumors, but the roles of TPGS2 in tumor immunity remain unclear. METHODS: The research data were mainly sourced from The Cancer Genome Atlas. The data were analyzed to identify potential correlations between TPGS2 expression and survival, gene alterations, the tumor mutational burden (TMB), microsatellite instability (MSI), immune infiltration, and various immune-related genes across various cancers. The Wilcoxon rank-sum test was used to identify the significance. A log-rank test and univariate Cox regression analysis were performed to assess the survival state of the patients. Spearman's correlation coefficients were used to show the correlations. RESULTS: TPGS2 exhibited abnormal expression patterns in most types of cancers, and has promising prognostic potential in adrenocortical carcinoma and liver hepatocellular carcinoma. Further, TPGS2 expression was significantly correlated with molecular and immune subtypes. Moreover, the single-cell analyses showed that the expression of TPGS2 was associated with the cell cycle, metastasis, invasion, inflammation, and DNA damage. In addition, the immune cell infiltration analysis and gene-set enrichment analysis demonstrated that a variety of immune cells and immune processes were associated with TPGS2 expression in various cancers. Further, immune regulators, including immunoinhibitors, immunostimulators, the major histocompatibility complex, chemokines, and chemokine receptors, were correlated with TPGS2 expression in different cancer types. Finally, the TMB and MSI, which have been identified as powerful predictors of immunotherapy, were shown to be correlated with the expression of TPGS2 across human cancers. CONCLUSIONS: TPGS2 is aberrantly expressed in most cancer tissues and might be associated with immune cell infiltration in the tumor microenvironment. TPGS2 could serve not only as a biomarker for predicting clinical outcomes, but also as a promising biomarker for evaluating and developing new approaches to immunotherapy in many types of cancers, especially colon adenocarcinoma and stomach adenocarcinoma.
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Cuproptosis-Related Ferroptosis Gene Signature: A Prognostic Tool for Colon Cancer Patients.
BACKGROUND: Ferroptosis and cuprotosis, two distinct mechanisms of programmed cell death, play key roles in colon cancer development. This study aimed to construct a prognostic model for predicting colon adenocarcinoma (COAD) prognosis based on the differential expression of cuproptosis-related ferroptosis genes (CFRGs). METHODS AND RESULTS: Transcriptomic data and clinical data of COAD patients were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. A combination of methods, including analysis of variance, Pearson correlation analysis, Least absolute shrinkage and selection operator (LASSO) algorithm, and Cox regression was used to construct the CFRGs signatures. In addition, multiple algorithmic strategies were employed to explore the potential association between risk scores and immune infiltration features. Single-cell datasets were used to analyze model genes. Somatic mutations and drug sensitivities were compared across risk groups. Immunohistochemical analysis was performed to verify the expression of the main characterized genes. We identified eight pivotal genes in constructing the CFRGs signature. Single-cell RNA sequencing revealed differential expression of CFRGs in the COAD tumor microenvironment. The nomogram confirmed that risk scoring serves as an independent prognostic factor for COAD. The high-risk group exhibited higher immune cell and stromal cell infiltration, as well as immune checkpoint expression. Patients in the high-risk group may benefit from olanzapine administration. Both RT-PCR and immunohistochemistry have confirmed that the expression levels of GLS and YAP1 in COAD tissues are significantly higher than those in adjacent non-cancerous tissues. CONCLUSIONS: The CFRGs risk prognosis model can effectively predict patients' immune infiltration and immunotherapy response, providing a new reference basis for individualized treatment plans for COAD patients.
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Single cell map of the adult female mouse urethra reveals epithelial and stromal macrophages with distinct functional identities.
Epithelial linings at mucosal sites act in concert with resident immune cells to direct host defense. The epithelial lining of the urethra is an understudied mucosal barrier with emerging roles in antimicrobial defense during urinary tract infections. Here, we present a comprehensive cellular atlas of the adult female mouse urethra, focusing on epithelial and resident immune cells. Single cell RNA-sequencing revealed two distinct macrophage populations compartmentalized within the epithelium and stroma. Epithelial-associated macrophages display a highly dendritic morphology and populate the urethral lining in increasing numbers over the course of development. Epithelial-associated macrophages express Cx3cr1, MHCII genes, Cd74 and Aif1/Iba-1, representing an activated macrophage type (Mac-Activated) enriched for pathways involved in antigen presentation and the inflammatory response. In contrast, stromal macrophages express the scavenging receptors Mrc1/Cd206, Lyve1, Cd163 and Mgl2/Cd301b and display a signature enriched for endocytic function (Mac-Endocytic), vasculature development and tissue homeostasis. We identified epithelial cells in the urethral lining and associated glands expressing the monocyte chemoattractant genes Cx3cl1 and Cxcl17. Chemoattractant gene expression in the urethral epithelium follows a proximal-distal gradient which correlates with the increasing density of epithelial-associated macrophages expressing the receptor Cx3cr1 along the proximal-distal axis of the urethra. The study delineates spatially compartmentalized macrophage subsets in the urethra and implicates epithelial-derived chemokines in the establishment of macrophage positioning and functional specialization along the urethral axis.