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Single-cell profiling of peripheral and local immune compartments reveal unique genotype-independent prognostic immune signatures across isocitrate dehydrogenase-stratified glioma.
BACKGROUND: Solid tumor immune suppression requires cooperation of tumor cells, local immune cells, peripheral circulating immune cells, and evolution of immune cell trajectories between peripheral and local environments. This study addresses a significant knowledge gap by characterizing peripheral and local immune environments in isocitrate dehydrogenase (IDH) Mutant (IDH-Mut) and IDH wildtype (IDH-WT) gliomas and defines novel immunological states with prognostic relevance across the glioma landscape. METHODS: We analyzed local and peripheral immune phenotypes in a cohort of 18 (6 IDH-Mut and 12 IDH-WT) gliomas with distinct genetic characteristics using paired human tumor and peripheral blood mononuclear cells (PBMCs) with single-cell RNA-sequencing (scRNA-seq). RESULTS: Our analyses revealed unique intratumoral and peripheral immune cellular ontogenies, including naïve CD4+ T cell enrichment in the IDH-Mut peripheral immune compartment, monocyte enrichment in IDH-WT glioma PBMCs, and emergence of a unique population of GZMH+ CD8+ T cells preferentially in the IDH-Mut microenvironment. Additionally, we found upregulation of TNF-α signaling and inflammatory response pathways in IDH-Mut--glioma-associated peripheral lymphoid cells versus IDH-WT tumors and identified a novel population of microglia-like cells in the peripheral blood of glioma patients with complement-interfacing characteristics. Applying intratumoral transcriptomic deconvolution via The Cancer Genome Atlas revealed genotype-independent, prognostic immune signatures across the malignant glioma landscape. CONCLUSIONS: This study reveals variable expression of immune phenotypes in adult gliomas stratified by IDH status and characterizes immune compartment and genotype-dependent differences in the immunologic glioma landscape. These genotype-dependent, tumor and circulating immune ontogenies should guide future diagnostic and immunotherapeutic considerations in malignant glioma.
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Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma.
The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant, including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here, we present the first comprehensive single-cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple in vitro models of benign and malignant mesothelial cells, and characterise these through comparison with in vivo transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at the single-cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. It has already enabled us to shed light on the transdifferentiation of mesothelial cells, allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro.
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Single-cell atlas of colonic CD8+ T cells in ulcerative colitis.
Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8+ T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8+ T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8+ T-cell composition, including expanded effector and post-effector terminally differentiated CD8+ T cells. While UC-associated CD8+ effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8+ T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8+ T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model.
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Apatinib inhibits glioma cell malignancy in patient-derived orthotopic xenograft mouse model by targeting thrombospondin 1/myosin heavy chain 9 axis.
We determined the antitumor mechanism of apatinib in glioma using a patient-derived orthotopic xenograft (PDOX) glioma mouse model and glioblastoma (GBM) cell lines. The PDOX mouse model was established using tumor tissues from two glioma patients via single-cell injections. Sixteen mice were successfully modeled and randomly divided into two equal groups (n = 8/group): apatinib and normal control. Survival analysis and in vivo imaging was performed to determine the effect of apatinib on glioma proliferation in vivo. Candidate genes in GBM cells that may be affected by apatinib treatment were screened using RNA-sequencing coupled with quantitative mass spectrometry, data mining of The Cancer Genome Atlas, and Chinese Glioma Genome Atlas databases, and immunohistochemistry analysis of clinical high-grade glioma pathology samples. Quantitative reverse transcription-polymerase chain reaction (qPCR), western blotting, and co-immunoprecipitation (co-IP) were performed to assess gene expression and the apatinib-mediated effect on glioma cell malignancy. Apatinib inhibited the proliferation and malignancy of glioma cells in vivo and in vitro. Thrombospondin 1 (THBS1) was identified as a potential target of apatinib that lead to inhibited glioma cell proliferation. Apatinib-mediated THBS1 downregulation in glioma cells was confirmed by qPCR and western blotting. Co-IP and mass spectrometry analysis revealed that THBS1 could interact with myosin heavy chain 9 (MYH9) in glioma cells. Simultaneous THBS1 overexpression and MYH9 knockdown suppressed glioma cell invasion and migration. These data suggest that apatinib targets THBS1 in glioma cells, potentially via MYH9, to inhibit glioma cell malignancy and may provide novel targets for glioma therapy.
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Comprehensive single-cell analysis of triple-negative breast cancer based on cDC1 immune-related genes: prognostic model construction and immunotherapy potential.
BACKGROUND: Various components of the immunological milieu surrounding tumors have become a key focus in cancer immunotherapy research. There are currently no reliable biomarkers for triple-negative breast cancer (TNBC), leading to limited clinical benefits. However, some studies have indicated that patients with TNBC may achieve better outcomes after immunotherapy. Therefore, this study aimed to identify molecular features potentially associated with conventional type 1 dendritic cell (cDC1) immunity to provide new insights into TNBC prognostication and immunotherapy decision-making. METHODS: Single-cell ribonucleic acid sequencing data from the Gene Expression Omnibus database were analyzed to determine which genes are differentially expressed genes (DEGs) in cDC1s. We then cross-referenced cDC1-related DEGs with gene sets linked to immunity from the ImmPort and InnateDB databases to screen for the genes linked to the immune response and cDC1s. We used univariate Cox and least absolute shrinkage and selection operator regression analyses to construct a risk assessment model based on four genes in patients with TNBC obtained from the Cancer Genome Atlas, which was validated in a testing group. This model was also used to assess immunotherapy responses among the IMvigor210 cohort. We subsequently utilized single sample Gene Set Enrichment Analysis, CIBERSORT, and ESTIMATE to analyze the immunological characteristics of the feature genes and their correlation with drug response. RESULTS: We identified 93 DEGs related to the immune response and cDC1s, of which four (IDO1, HLA-DOB, CTSD, and IL3RA) were substantially linked to the overall survival rate of TNBC patients. The risk assessment model based on these genes stratified patients into high- and low-risk groups. Low-risk patients exhibited enriched ''hot tumor'' phenotypes, including higher infiltration of memory-activated CD4 + T cells, CD8 + T cells, gamma delta T cells, and M1 macrophages, as well as elevated immune checkpoint expression and tumor mutational burden, suggesting potential responsiveness to immunotherapy. Conversely, high-risk patients displayed "cold tumor" characteristics, with higher infiltration of M0 and M2 macrophages and lower immune scores, which may be poorer in response to immunotherapy. However, experimental validation and larger clinical studies are necessary to confirm these findings and explore the underlying mechanisms of the identified genes. CONCLUSION: This study developed a robust risk assessment model using four genes that effectively forecast the outcome of patients with TNBC and have the potential to guide immunotherapy. This model provided new theoretical insights for knowing the TNBC immune microenvironment and developing personalized treatment strategies.
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A Macrophage/Monocyte-Related Four-Gene Signature for Prognostic Assessment of Uveal Melanoma: BTBD6, C2CD4B, CCL24, and S100A4.
BACKGROUND: Uveal melanoma (UVM) is a highly malignant ocular tumor with a poor prognosis. Macrophages and monocytes in the tumor microenvironment promote immune escape, angiogenesis, and metastasis. Thus, exploring their roles may provide insights into UVM progression. METHODS: The Cancer Genome Atlas (TCGA) was accessed to obtain the data of mRNA expression and follow-up data of UVM, and UVM single-cell profiles were downloaded to cluster cells by annotation of single-cell marker genes. The differentially expressed genes (DEGs) in macrophage/monocyte cells compared to other cell types were revealed. ssGSEA was applied to compute the score of DEGs and to reveal the genes for WGCNA in UVM. A prognostic risk model for UVM was constructed by uni/multivariate Cox and LASSO regression analyses to reveal the differential overall survival status. Further cellular validations were conducted to examine the effects of core genes in UVM. TIMER tool was applied for the analysis of immune cell infiltration levels in UVM. Chemotherapeutic drug sensitivity in UVM was assessed with the pRRophetic package. RESULTS: Six cell subpopulations were identified in the UVM samples, among which macrophage/monocyte cells were more predominant. Kaplan-Meier curves showed that UVM patients in the group of high RiskScore (consisting of the genes BTBD6, C2CD4B, CCL24, and S100A4) presented a poorer prognosis, higher infiltration of monocytic lineage, T cells, CD8 T cells, cytotoxic lymphocytes, and higher expression of immune checkpoint-related genes. A significant negative correlation between RiskScore and the IC50 of XMD8-85, lapatinib, roscovitine, salubrinal, bexarotene, LFM-A13, FTI-277, and TGX221 chemotherapeutic agents was further noticed. CONCLUSION: In this study, we computationally identified genes associated with both disease progression and macrophage/monocyte-related characteristics in UVM and constructed a prognostic risk model with predicted immune infiltration patterns. These findings generate testable hypotheses that may inform future experimental studies on the immune mechanisms underlying UVM.
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BCL2A1‑ and G0S2‑driven neutrophil extracellular traps: A protective mechanism linking preeclampsia to reduced breast cancer risk.
Preeclampsia has been associated with a reduced risk of breast cancer (BC), but the mechanisms underlying this relationship remain unclear. It has been suggested that neutrophil extracellular traps (NETs), which are released upon neutrophil activation, play a key role in both preeclampsia and BC. To investigate this link, the single‑cell RNA sequencing dataset GSE173193 was analyzed and upregulated genes BCL2A1 and G0/G1 switch gene 2 (G0S2) were identified in neutrophils from preeclamptic placentas. These findings were validated using reverse transcription‑quantitative PCR and western blotting. Combined analyses of preeclampsia and BC tissues, from Gene Expression Omnibus (GSE24129) and The Cancer Genome Atlas databases respectively, identified 2,040 upregulated differentially expressed genes, including BCL2A1 and G0S2. Furthermore, these genes showed clinical relevance to BC, as demonstrated by Receiver Operating Characteristic curve, survival analyses and weighted gene co‑expression network analysis. Functional experiments revealed that overexpression of BCL2A1 and G0S2 increased NET release and inhibited BC cell proliferation, invasion and migration. The present study provides novel insights into the shared molecular pathways of preeclampsia and BC, emphasizing NETs as a potential protective mechanism as increased NET production in preeclampsia may contribute to a reduced BC risk by influencing tumor progression and offer avenues for further research into therapeutic interventions.
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Transcriptional factor ZMYM3 promotes hepatocellular carcinoma metastasis by upregulating CTTN and inducing invadopodia formation.
Hepatocellular carcinoma (HCC) is characterized by high invasiveness and metastatic potential, leading to poor prognosis. Therefore, understanding the molecular mechanisms underlying HCC invasion and metastasis is essential for developing effective therapeutic strategies. This study investigates the role of ZMYM3 in HCC invasion and metastasis. Analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, along with immunohistochemistry, revealed that ZMYM3 is upregulated in HCC tissues and associated with recurrence and poor prognosis. Single-cell sequencing data indicated higher ZMYM3 expression in portal vein tumor thrombus compared to primary lesions, suggesting its involvement in metastasis. Functional assays demonstrated that ZMYM3 enhances HCC cell proliferation, invasion, and metastasis. RNA sequencing identified that ZMYM3 promotes invadopodia formation and epithelial-mesenchymal transition (EMT) in HCC cells. Further chromatin immunoprecipitation sequencing and mechanistic studies showed that ZMYM3 directly binds to the promoter of CTTN, a key gene regulating invadopodia formation, thereby increasing its expression. This upregulation contributes to the enhanced invasive and metastatic capabilities of HCC cells. Our findings identify ZMYM3 overexpression as a predictor of high recurrence risk and poor prognosis in HCC patients. Mechanistically, ZMYM3 promotes invadopodia formation primarily through the upregulation of CTTN, thereby augmenting the invasive and metastatic potential of HCC cells. These results highlight the critical role of ZMYM3 in HCC progression and metastasis. ZMYM3 promotes hepatocellular carcinoma metastasis by upregulating CTTN and inducing invadopodia formation.
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The Pediatric Cell Atlas: Defining the Growth Phase of Human Development at Single-Cell Resolution.
Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.
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Single-cell transcriptomics of adult macaque hippocampus reveals neural precursor cell populations.
The extent to which neurogenesis occurs in adult primates remains controversial. In this study, using an optimized single-cell RNA sequencing pipeline, we profiled 207,785 cells from the adult macaque hippocampus and identified 34 cell populations comprising all major hippocampal cell types. Analysis of their gene expression, specification trajectories and gene regulatory networks revealed the presence of all key neurogenic precursor cell populations, including a heterogeneous pool of radial glia-like cells (RGLs), intermediate progenitor cells (IPCs) and neuroblasts. We identified HMGB2 as a novel IPC marker. Comparison with mouse single-cell transcriptomic data revealed differences in neurogenic processes between species. We confirmed that neurogenesis is recapitulated in ex vivo neurosphere cultures from adult primates, further supporting the existence of neural precursor cells (NPCs) that are able to proliferate and differentiate. Our large-scale dataset provides a comprehensive adult neurogenesis atlas for primates.