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XBP1 impacts lung adenocarcinoma progression by promoting plasma cell adaptation to the tumor microenvironment.
Background: The activation of X-box binding protein 1 (XBP1) plays an essential role in the unfolded protein response (UPR) of the endoplasmic reticulum (ER). XBP1 is commonly expressed in various tumors and is closely related to tumorigenesis and progression. However, the role of XBP1 in lung adenocarcinoma (LUAD), especially the prognostic value of its alternative splicing isoforms, remains largely unknown. Methods: The LUAD datasets were retrieved from the The Cancer Genome Atlas, ArrayExpress and Gene Expression Omnibus. GEPIA2 and meta-analysis were employed to explore the prognostic value, and bioinformatics analysis with the TIMER2.0 database was used to investigate immune cell infiltration. We performed single-cell analyses to identify cell types with high XBP1 expression. In addition, polymerase chain reaction (PCR) and DNA sequencing were performed to verify the authenticity of the new spliceosome. Results: In this study, we found that high expression of XBP1 was significantly associated with a good prognosis, and XBP1 expression was significantly positively correlated with B cell infiltration in LUAD. In addition, we found that high-level expression of a novel splicing isoform, XBP1 (XBP1-003), improved the prognosis of LUAD. Protein structural analysis demonstrated that XBP1-003 has several specific protein domains that are different from those of other XBP1 isoforms, indicating a unique function of this isoform in LUAD. Conclusion: All these results suggest that XBP1 plays an antitumorigenic role in LUAD through alternative splicing, which may be related to the adaptation of plasma cells. This sheds new light on the potential strategy for LUAD prognosis evaluation and immunotherapy.
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Single-cell characterization of self-renewing primary trophoblast organoids as modeling of EVT differentiation and interactions with decidual natural killer cells.
BACKGROUND: Extravillous trophoblast cell (EVT) differentiation and its communication with maternal decidua especially the leading immune cell type natural killer (NK) cell are critical events for placentation. However, appropriate in vitro modelling system and regulatory programs of these two events are still lacking. Recent trophoblast organoid (TO) has advanced the molecular and mechanistic research in placentation. Here, we firstly generated the self-renewing TO from human placental villous and differentiated it into EVTs (EVT-TO) for investigating the differentiation events. We then co-cultured EVT-TO with freshly isolated decidual NKs for further study of cell communication. TO modelling of EVT differentiation as well as EVT interaction with dNK might cast new aspect for placentation research. RESULTS: Single-cell RNA sequencing (scRNA-seq) was applied for comprehensive characterization and molecular exploration of TOs modelling of EVT differentiation and interaction with dNKs. Multiple distinct trophoblast states and dNK subpopulations were identified, representing CTB, STB, EVT, dNK1/2/3 and dNKp. Lineage trajectory and Seurat mapping analysis identified the close resemblance of TO and EVT-TO with the human placenta characteristic. Transcription factors regulatory network analysis revealed the cell-type specific essential TFs for controlling EVT differentiation. CellphoneDB analysis predicted the ligand-receptor complexes in dNK-EVT-TO co-cultures, which relate to cytokines, immunomodulation and angiogenesis. EVT was known to affect the immune properties of dNK. Our study found out that on the other way around, dNKs could exert effects on EVT causing expression changes which are functionally important. CONCLUSION: Our study documented a single-cell atlas for TO and its applications on EVT differentiation and communications with dNKs, and thus provide methodology and novel research cues for future study of human placentation.
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Single-cell transcriptomics reveal oxidative phosphorylation and oxidative stress in the superior temporal plane of non-syndromic cleft lip and palate fetuses.
AIM: Non-syndromic cleft lip and palate (NSCLP) is a common congenital disability that causes morphological and functional abnormalities in the craniofacial region. Many studies have focused on clinical treatments and surgical aspects, but there has been limited investigation into the neural mechanisms in individuals with NSCLP. Therefore, it remains unclear whether developmental abnormalities in the brains of NSCLP fetuses exist. MATERIALS AND METHODS: To investigate the presence of developmental abnormalities in the brains of NSCLP fetuses, we performed single-nucleus RNA sequencing (snRNA-seq) on the superior temporal plane (STP) from three NSCLP fetuses and three normal fetuses. Samples were collected at 17-23 gestational weeks. Real-time quantitative PCR (RT-qPCR) and immunofluorescence were performed to validate further phenotypes identified in the sequencing data. KEY FINDINGS: Following dimensionality reduction and clustering, we identified seven distinct cell types. Cell abundance changes revealed that excitatory neurons, inhibitory neurons, and astrocytes varied dramatically. We further identified the abnormally increased levels of oxidative phosphorylation (OXPHOS) and oxidative stress in the STP of NSCLP fetuses. Further investigation determined that a specific subpopulation of inhibitory neurons, InN6, is closely associated with altered OXPHOS and oxidative stress, potentially contributing to abnormal brain development in NSCLP. Finally, immunofluorescence and RT-qPCR results confirmed the abnormal increase in OXPHOS and oxidative stress in the NSCLP fetuses' brain. SIGNIFICANCE: This study provides a single-cell atlas of STP in the NSCLP fetuses, revealing increased OXPHOS and oxidative stress in the NSCLP fetal brain. These findings provide new insights into the pathological mechanisms of the brain in NSCLP.
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Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma.
Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG frequently develops in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-sequencing, we identify ectopic expression of neuromuscular molecules in MG-type thymoma. These molecules are found within a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we name neuromuscular mTECs (nmTECs). MG-thymoma also exhibits microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicts the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma is further confirmed immunohistochemically and by cellular composition estimation from the MG-thymoma transcriptome. Altogether, this study suggests that nmTECs have a significant function in MG pathogenesis via ectopic expression of neuromuscular molecules.
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A Novel Cholesterol Metabolism-Related lncRNA Signature Predicts the Prognosis of Patients with Hepatocellular Carcinoma and Their Response to Immunotherapy.
BACKGROUND: The survival rate of hepatocellular carcinoma (HCC) is low and the prognosis is poor. Metabolic reprogramming is still an emerging hallmark of cancer, and reprogramming of cholesterol metabolism plays a crucial action in tumor pathogenesis. Increasing evidence suggests that cholesterol metabolism affects the cell proliferation, invasion, migration, and resistance to chemotherapy of HCC. To date, no long noncoding RNA (lncRNA) signature associated with cholesterol metabolism has been developed to predict the outcome of patients with HCC. METHODS: The RNA-seq data as well as the prognostic and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We conducted univariate and multivariate analyses to assess cholesterol metabolism-related lncRNAs correlated with the prognosis of patients with HCC in order to construct a prognostic signature. Functional differences between low- and high-risk groups were investigated using genomic enrichment analysis (GSEA). Kaplan-Meier (KM) curves were applied to explore the overall survival (OS) of the low- and high-risk groups. Single-sample genomic enrichment analysis (ssGSEA) was applied to investigate the association between this predictive signature and immune function. We subsequently examined how this signature relates to treatment response in HCC patients. RESULTS: A prognostic signature comprising six lncRNAs related to cholesterol metabolism was constructed (AC124798.1, AL031985.3, AC103760.1, NRAV, WAC-AS1 and AC022613.1). We found that low-risk groups showed a better prognosis than high-risk groups. In HCC patients, the cholesterol metabolism-related lncRNA signature may be served as an independent prognostic factor. Cholesterol metabolism-related lncRNA signature had higher diagnostic efficiency compared to clinicopathologic variables. After stratifying patients according to different clinicopathological variables, patients with low-risk had a longer OS compared with high-risk patients. The ssGSEA demonstrated that this signature was closely related to the immune status of HCC patients. GSEA analysis demonstrated that immune- and tumor-related pathways were predominantly enriched in the high-risk group. High-risk patients were more responsive to immune checkpoint inhibitors (ICIs) and conventional chemotherapeutic agents. CONCLUSIONS: This cholesterol metabolism-related lncRNA signature can predict the prognosis of HCC patients and guide the clinical management of HCC patients, including immunotherapy.
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Multi-omic analysis of androgen-deprived human testes reveals Sertoli cell regulation and niche reprogramming.
Testis development and male fertility depend on androgens, yet the mechanisms underlying their regulation of adult human testicular function remain poorly defined due to ethical and technical constraints. To address this, we leverage androgen-deprived adult human testes as a spontaneous model and construct a comprehensive multi-omics atlas integrating single-nucleus RNA sequencing, single-cell ATAC-seq, and spatial transcriptomics. Our analyses highlight androgen-regulated transcription factors critical for Sertoli cell function and identify Neuregulin 2 (NRG2) as an androgen-dependent niche factor secreted by Sertoli cells that promotes spermatogonial proliferation both in vivo and in vitro. We further observe that androgen deprivation triggers ectopic expression of the Sertoli cell marker WT1 in the testicular interstitium, reprogramming a subset of interstitial cells toward a Sertoli-like transcriptomic state. Together, these findings uncover molecular mechanisms of androgen regulation in the adult human testes and provide a valuable resource for advancing therapies for androgen-related infertility and reproductive disorders.
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Assessment of long non-coding RNA expression reveals novel mediators of the lung tumour immune response.
The tumour immune microenvironment is a crucial mediator of lung tumourigenesis, and characterizing the immune landscape of patient tumours may guide immunotherapy treatment regimens and uncover novel intervention points. We sought to identify the landscape of tumour-infiltrating immune cells in the context of long non-coding RNA (lncRNAs), known regulators of gene expression. We examined the lncRNA profiles of lung adenocarcinoma (LUAD) tumours by interrogating RNA sequencing data from microdissected and non-microdissected samples (BCCRC and TCGA). Subsequently, analysis of single-cell RNA sequencing data from lung tumours and flow-sorted healthy peripheral blood mononuclear cells identified lncRNAs in immune cells, highlighting their biological and prognostic relevance. We discovered lncRNA expression patterns indicative of regulatory relationships with immune-related protein-coding genes, including the relationship between AC008750.1 and NKG7 in NK cells. Activation of NK cells in vitro was sufficient to induce AC008750.1 expression. Finally, siRNA-mediated knockdown of AC008750.1 significantly impaired both the expression of NKG7 and the anti-tumour capacity of NK cells. We present an atlas of cancer-cell extrinsic immune cell-expressed lncRNAs, in vitro evidence for a functional role of lncRNAs in anti-tumour immune activity, which upon further exploration may reveal novel clinical utility as markers of immune infiltration.
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Detection of Immune Microenvironment Changes and Immune-Related Regulators in Langerhans Cell Histiocytosis Bone Metastasis.
The inflammation/immune response pathway is considered a key contributor to the development of Langerhans cell histiocytosis (LCH) bone metastasis. However, the dynamic changes in the immune microenvironment of LCH bone metastasis and critical regulators are still unclear. Expression profiling by arrays of GSE16395, GSE35340, and GSE122476 was applied to detect the immune microenvironment changes in the development of LCH bone metastasis. The single-cell high-throughput sequencing of GSE133704, involved in LCH bone lesions, was analyzed. The online database Metascape and gene set variation analysis (GSVA) algorithms were used to detect the gene function of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein-protein interaction (PPI) network of hub regulators was constructed by the STRING database. In these results, key immune cells, such as Tem cells, NK T cells, CD8(+) T cells, and Th1 cells, were identified in LCH bone metastasis. These genes, which include LAG3, TSPAN5, LPAR5, VEGFA, CXCL16, CD74, and MARCKS, may significantly correlate with the cellular infiltration of B cells, aDCs, pDCs, cytotoxic cells, T cells, CD8+ T cells, T helper cells, and Tcm cells. In conclusion, our study constructed an atlas of the immune microenvironment of LCH bone metastasis. Genes including LAG3, TSPAN5, LPAR5, VEGFA, CXCL16, CD74, and MARCKS may be involved in the development of LCH bone metastasis. The hub gene-immune cell interactive map may be a potential prognostic biomarker for the progression of LCH bone metastasis and synergetic targets for immunotherapy in LCH patients.
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Predicting Prognosis and Immunotherapy Response in Glioblastoma (GBM) With a 5-Gene CAF-Risk Signature.
BACKGROUND: Cancer-associated fibroblasts (CAF) represent significant constituents within the extracellular matrix (ECM) across a range of cancers. Nevertheless, there exists a scarcity of direct proof concerning the function of CAF in glioblastoma (GBM). AIMS: This study endeavors to probe the participation of CAF in GBM by developing and validating a CAF-risk signature and exploring its correlation with immune infiltration and immunotherapy responsiveness. METHODS AND RESULTS: To fulfill these objectives, mRNA expression profiles of GBM samples and their corresponding clinical data were retrieved from two databases. First, stromal CAF-associated genes were identified by weighted gene co-expression network analysis (WGCNA). This method constructs co-expression networks and pinpoints gene modules with similar expression patterns to detect relevant genes. Subsequently, a CAF-risk signature was established via univariate and LASSO Cox regression analyses. Thereafter, gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were carried out to investigate the underlying molecular mechanisms. The immune status was evaluated with several R packages, and the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was utilized to assess the response to immunotherapy. Validation was performed using single-cell RNA sequencing (scRNA) datasets, the Cancer Cell Line Encyclopedia (CCLE), and the Human Protein Atlas (HPA). Eventually, a 5-gene (ITGA5, MMP14, FN1, COL5A1, and COL6A1) prognostic CAF model was constructed. Notably, immune infiltration analysis demonstrated a significant correlation between Treg, Macrophage, and CAF risk scores. Moreover, TIDE analysis suggested a decreased responsiveness to immunotherapy in high CAF-risk patients. In addition, GSEA showed significant enrichment of the transforming growth factor alpha (TGF-α), inflammatory response, and epithelial-mesenchymal transition (EMT) pathways in this subgroup. Finally, the validation through scRNA, CCLE, and HPA datasets confirmed these findings. CONCLUSION: The 5-gene CAF-risk signature exhibited accurate prognostic predictions and efficiently evaluated clinical immunotherapy responses among GBM patients. These results offer robust evidence regarding the implication of CAF in GBM and underscore the potential clinical value of personalized anti-CAF therapies in conjunction with immunotherapy.
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Targeting exercise-related genes and placental growth factor for therapeutic development in head and neck squamous cell carcinoma.
BACKGROUND: Human cancers, including head and neck squamous cell carcinoma (HNSCC), are complex and heterogeneous diseases driven by uncontrolled cell growth and proliferation. Post-translational modifications (PTMs) of proteins play a crucial role in cancer progression, making them a promising target for pharmacological intervention. This study aims to identify key exercise-related genes with prognostic value in HNSCC through comprehensive bioinformatics analysis, with a particular focus on the therapeutic potential of placental growth factor (PIGF). METHODS: Transcriptome data for HNSCC were obtained from The Cancer Genome Atlas (TCGA) database. Differently expressed genes (DEGs) were identified and analyzed for their prognostic significance. Exercise-related gene sets were retrieved from the Gene Set Enrichment Analysis (GSEA) database. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA, were conducted. The biological functions and clinical implications of key genes were further explored through single-gene expression analysis, immune infiltration analysis, and in vitro cellular experiments. RESULTS: The study identified exercise-related genes associated with survival prognosis in HNSCC. GO and KEGG pathway analyses highlighted the biological functions of these genes, and Kaplan-Meier survival curves confirmed their prognostic value. PIGF expression analysis using TCGA data showed its diagnostic potential, with higher expression linked to advanced tumor stages. Single-cell sequencing revealed PIGF's role in the tumor microenvironment. In vitro experiments demonstrated that PIGF plays a pivotal role in enhancing cell proliferation and colony formation in HNSCC, with PIGF knockdown significantly impairing these functions, highlighting its importance in tumor growth regulation. Additionally, PIGF's predictive performance in drug sensitivity across cancer datasets suggests its potential as a pharmacological target, offering opportunities to modulate the immune microenvironment and improve therapeutic outcomes in cancer treatment. CONCLUSION: This study provides new insights into the molecular mechanisms underlying HNSCC and identifies exercise-related genes, particularly PIGF, as promising biomarkers for clinical treatment and personalized medicine. By focusing on PTMs and their role in cancer progression, our findings suggest that targeting PIGF may offer innovative therapeutic strategies.