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Cancer-Associated Fibroblasts in Gastric Cancer Regulate Macrophage Polarization through RCN3 Pathway.
OBJECTIVE: To explore the role and molecular mechanism of cancer-associated fibroblasts (CAFs) in the tumor microenvironment of gastric cancer (GC). METHODS: The expression of CAFs in GC patients was first assessed for abundance, and survival analysis was performed. Subsequently, The Cancer Genome Atlas (TCGA) data were used for differential analysis, survival analysis, and EPIC analysis, while single-cell data (GSE183904) were downloaded for differential analysis of CAFs. Clinical data pooling, univariate and multivariate Cox analysis, and immunofluorescence were carried out on clinical GC tissue samples to explore RCN3 expression within patient CAFs. Western blot and quantitative polymerase chain reaction (qPCR) were used to detect the expression of RCN3. The relationship between RCN3, PCSK6, and STAT1 was explored by chromatin immunoprecipitation (CHIP) experiments, and the effects of the genes on macrophage polarization were detected by detecting biomarkers of biological M1/M2. RESULTS: CAFs in GC were found to be significantly higher compared to the normal group. Revealing the results of TCGA differential analysis, it was observed that GC exhibited a substantial upregulation in the expression levels of RCN3. The clinical statistics indicate a positive correlation between an elevated level of RCN3 expression and the T-stage classification of tumor size. In addition, RCN3 was found to have a significant impact on the overall survival of patients with gastric cancer, acting as an independent prognostic indicator. Analysis of single-cell data showed high expression of PCSK6 in macrophages, and immunofluorescence staining of samples from GC patients showed increased expression of PCSK6 on the cell membranes of macrophages in GC tissues. The subsequent cellular experiments confirmed RCN3 protein can regulate the expression of PCSK6, and PCSK6 regulates macrophage polarization through STAT1. CONCLUSIONS: CAFs regulate macrophage polarization through the RCN3/PCSK6/STAT1 pathway in GC.
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Senescence-related immunosuppressive gene MFAP2 orchestrates stromal-immune crosstalk and immunotherapy resistance in gastric cancer.
BACKGROUND: Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, with poor prognosis and immune checkpoint inhibitor (ICI) resistance mediated by immune escape. Senescence-related immunosuppressive genes (SRIGs) regulate the tumor microenvironment (TME); however, their hub genes and prognostic value in GC remain unclear. This study aimed to identify hub SRIGs and explore their significance. METHODS: Transcriptomic, single-cell RNA sequencing, and spatial transcriptomic data of GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. Weighted gene co-expression network analysis and Pearson correlation analysis were used to screen for SRIGs. Eight machine learning algorithms identified the hub SRIG, which was validated by RT-qPCR, immunohistochemistry, and clinical samples. Pseudotime trajectory, CellChat, and molecular docking analyses were used to explore the underlying mechanisms and potential drugs. A pan-cancer analysis was used to verify its generalizability. RESULTS: A senescence-related immunosuppressive signature was constructed, stratifying GC into two subtypes with distinct TME and prognosis. Microfibril-associated protein 2 (MFAP2) was identified as the hub SRIG, significantly upregulated in GC, and an independent prognostic risk factor. It was specifically expressed in extracellular matrix cancer-associated fibroblasts (eCAFs), driving their differentiation and extracellular matrix (ECM) remodeling. MFAP2⁺ eCAFs promoted M2 macrophage polarization via CSF1-CSF1R and C3-C3AR1 axes, mediating immune escape and ICI resistance. AZD4547 and MK-2461 were potential targeted drugs. Pan-cancer analysis confirmed the ubiquitous oncogenic role of MFAP2. CONCLUSIONS: MFAP2 is a hub SRIG linking eCAFs, ECM remodeling, and immune escape in GC. It serves as a reliable prognostic and ICI resistance predictor and potential therapeutic target, providing a basis for precision therapy in GC.
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A single-cell atlas of CD19 chimeric antigen receptor T cells.
Li et al. present a resource of single-cell RNA sequencing (scRNA-seq) data from the infusion products of relapsed or refractory large B cell lymphoma (rrLBCL) patients treated with standard-of-care axicabtagene ciloleucel and identify features that are significantly different between products from responders and non-responders at 3-month followup by PET/CT, an important landmark for long-term outcomes.
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Integrated Analysis of PSMB8 Expression and Its Potential Roles in Hepatocellular Carcinoma.
BACKGROUND: Hepatocellular carcinoma (HCC) represents a highly aggressive malignancy with significant global health implications. The proteasome subunit beta type-8 (PSMB8) gene, known for its association with hepatitis B virus susceptibility, has emerged as a potential regulator of tumor progression. However, its functional role and clinical significance in HCC remain poorly characterized. METHODS: We conducted a comprehensive multi-omics analysis to elucidate the role of PSMB8 in HCC. PSMB8 expression profiles were derived from The Cancer Genome Atlas and validated using the GSE76427 dataset. Prognostic significance was assessed through Kaplan-Meier survival analysis. Then, we systematically evaluated the relationships between PSMB8 expression and clinicopathological features, somatic mutations, immune cell infiltration, immune regulatory genes, and immune checkpoint responses. Single-cell RNA sequencing data from the Tumor Immune Single-cell Hub database were analyzed to determine cell type-specific PSMB8 expression. Tissue-level validation was performed using multiplex immunofluorescence staining on HCC tissue microarrays. RESULTS: PSMB8 demonstrated significant overexpression in HCC tissues and exhibited strong prognostic value. Single-cell analysis revealed predominant PSMB8 expression in T and B cell populations. Notably, PSMB8 expression showed significant positive correlations with immune checkpoint molecules PD-L1/CD274 and CD27. Functional enrichment analysis implicated PSMB8 in multiple oncogenic pathways, particularly proteasome-related processes. CONCLUSION: Our findings position PSMB8 as a promising prognostic biomarker and potential therapeutic target in HCC. The observed associations with immune checkpoint molecules and proteasomal pathways suggest its potential role in modulating tumor immunity and protein homeostasis, warranting further investigation into its mechanistic contributions to HCC progression.
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Characterization of the microenvironment in different immune-metabolism subtypes of cervical cancer with prognostic significance.
Introduction: Immune cell infiltration and metabolic reprogramming may have great impact on the tumorigenesis and progression of malignancies. The interaction between these two factors in cervical cancer remains to be clarified. Here we constructed a gene set containing immune and metabolism related genes and we applied this gene set to molecular subtyping of cervical cancer. Methods: Bulk sequencing and single-cell sequencing data were downloaded from the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database respectively. Immune and metabolism related genes were collected from Immport and Kyoto encyclopedia of genes and genomes (KEGG) database respectively. Unsupervised consensus clustering was performed to identify the molecular subtypes. Cibersort was applied to evaluate the immune cells infiltration status. Differential expression analysis and Gene set enrichment analysis (GSEA) were performed to characterize the molecular pattern of different subtypes. Multivariate Cox regression analysis was used for prognosis prediction model construction and receiver operating characteristic (ROC) curve was used for performance evaluation. The hub genes in the model were verified in single-cell sequencing dataset and clinical specimens. In vitro experiments were performed to validate the findings in our research. Results: Three subtypes were identified with prognostic implications. C1 subgroup was in an immunosuppressive state with activation of mitochondrial cytochrome P450 metabolism, C2 had poor immune cells infiltration and was characterized by tRNA anabolism, and the C3 subgroup was in an inflammatory state with activation of aromatic amino acid synthesis. The area under the ROC curve of the constructed model was 0.8, which showed better performance than clinical features. IMPDH1 was found to be significantly upregulated in tumor tissue and it was demonstrated that IMPDH1 could be a novel therapeutic target in vitro. Discussion: In summary, our findings suggested novel molecular subtypes of cervical cancer with distinct immunometabolic profiles and uncovered a novel therapeutic target.
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Cancer-wide in silico analyses using differentially expressed genes demonstrate the functions and clinical relevance of JAG, DLL, and NOTCH.
Notch ligands [jagged (JAG) and, delta-like (DLL) families] and receptors [NOTCH family] are key regulators of Notch signaling. NOTCH signaling contributes to vascular development, tissue homeostasis, angiogenesis, and cancer progression. To elucidate the universal functions of the JAG, DLL, and NOTCH families and their connections with various biological functions, we examined 15 types of cancer using The Cancer Genome Atlas clinical database. We selected the differentially expressed genes (DEGs), which were positively correlated to the JAG, DLL, and NOTCH families in each cancer. We selected positive and negative hallmark signatures across cancer types. These indicated biological features associated with angiogenesis, hypoxia, KRAS signaling, cell cycle, and MYC targets by gene ontology and gene set enrichment analyses using DEGs. Furthermore, we analyzed single-cell RNA sequencing data to examine the expression of JAG, DLL, and NOTCH families and enrichment of hallmark signatures. Positive signatures identified using DEGs, such as KRAS signaling and hypoxia, were enriched in clusters with high expression of JAG, DLL, and NOTCH families. We subsequently validated the correlation between the JAG, DLL, and NOTCH families and clinical stages, including treatment response, metastasis, and recurrence. In addition, we performed survival analysis to identify hallmark signatures that critically affect patient survival when combining the expression of JAG, DLL, and NOTCH families. By combining the DEG enrichment and hallmark signature enrichment in survival analysis, we suggested unexplored regulatory functions and synergistic effects causing synthetic lethality. Taken together, our observations demonstrate the functions of JAG, DLL, and NOTCH families in cancer malignancy and provide insights into their molecular regulatory mechanisms.
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Developmental stage-specific localization of CK1α protein in the mouse ovary.
Casein kinase 1 alpha (CK1α), a conserved serine/threonine kinase, regulates diverse cellular processes including signal transduction, cell cycle progression, and DNA replication. To define its spatiotemporal dynamics during mammalian ovarian development, we systematically analyzed CK1α protein expression from embryonic day (E) 14.5 to postnatal day (P) 56 in the mouse ovary using Western blotting, immunofluorescence (IF) on tissue sections, and IF on isolated primary granulosa cells and oocytes. Reanalysis of published single-cell RNA sequencing data revealed progressive upregulation of Csnk1a1 transcripts from E9.5 through early postnatal stages. At the protein level, CK1α expression significantly increased from E14.5 to P56, with stabilization after P28. Immunofluorescence showed CK1α localized predominantly to oocytes within primordial follicles from E14.5 to P7. Starting at P7, CK1α expression expanded to include granulosa cells of developing primary and secondary follicles. Quantitative fluorescence analysis confirmed that CK1α signal in granulosa cells increased significantly from P7 onward, while the signal in the oocytes gradually decreased throughout development process. In vitro validation confirmed robust CK1α localization in both isolated granulosa cells and oocytes, co-localizing with FSHR and DDX4, respectively. This study provides the first comprehensive spatiotemporal atlas of CK1α expression in the wild-type developing mouse ovary, revealing stage-specific localization patterns that suggest distinct roles in oocyte maintenance and granulosa cell differentiation during folliculogenesis.
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YTHDC1 Promotes Stemness Maintenance and Malignant Progression in Head and Neck Squamous Cell Carcinoma.
BACKGROUND: YTH domain containing 1 (YTHDC1), an N6-methyladenosine (m6A) modification reading protein, plays a key role in regulating RNA translation and degradation. However, the role of YTHDC1 in head and neck squamous cell carcinoma (HNSCC) cancer stem cells remains largely unknown. This study is aimed at investigating the role of YTHDC1 in HNSCC and exploring its role in regulating cancer stem cells. METHODS: RNA sequencing was used to detect differentially expressed genes (DEGs) between SCC9 spheres and SCC9 cells and to uncover molecular pathways and target molecules associated with CSCs. We detected YTHDC1 expression in The Cancer Genome Atlas (TCGA) database data and clinical samples. Subsequently, YTHDC1 gene suppression assays were performed in HNSCC cell lines to investigate the effect of YTHDC1 on tumor cell stemness maintenance, proliferation, and migration capacity. To further confirm the role of YTHDC1 in regulating cancer stem cells in HNSCC, we analyzed online HNSCC single-cell transcriptomic data to investigate YTHDC1 expression patterns at the single-cell level and the correlation of these levels with the expression of stem cell markers. RESULTS: YTHDC1 expression levels were significantly upregulated in SCC9 spheres, and YTHDC1 was aberrantly expressed in HNSCC tumor tissues. The increased YTHDC1 expression was closely correlated with the clinical characteristics of HNSCC patients. YTHDC1 regulates the malignant phenotype of HNSCC in both in vivo and in vitro studies. Further single-cell transcriptomic data analysis revealed that YTHDC1 positively correlated with malignant epithelial cell stemness capacity at the single-cell level, and that YTHDC1 was involved in regulating stemness maintenance in HNSCC. CONCLUSIONS: These findings suggest that YTHDC1 may serve as a biomarker for stem maintenance and malignant progression in HNSCC, providing new insights into the treatment of cancer.
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A novel T-cell proliferation-associated gene predicts prognosis and reveals immune infiltration in patients with oral squamous cell carcinoma.
OBJECTIVE: Oral squamous cell carcinoma (OSCC) is a highly malignant tumour, and the prediction of its prognosis remains challenging. The prognostic value of T-lymphocyte proliferation regulators in OSCC remains to be explored. DESIGN: We integrated mRNA expression profiles and relevant clinical information of OSCC patients from The Cancer Genome Atlas database. The expression and function of T-lymphocyte proliferation regulators and their relationship with overall survival (OS) were analysed. The T-lymphocyte proliferation regulator signature was screened using univariate Cox regression and least absolute shrinkage and selection operator coefficients and used to construct models for prognosis and staging prediction as well as for immune infiltration analysis. Final validation was performed using single-cell sequencing database and immunohistochemical staining. RESULTS: Most T-lymphocyte proliferation regulators in the TCGA cohort exhibited different expression levels between OSCC and paracancerous tissues. A prognostic model constructed using the T-lymphocyte proliferation regulator signature (RAN, CDK1, and CDK2) was used to categorise patients into high- and low-risk groups. The OS was significantly lower in the high-risk group than the low-risk group (p < 0.01). The predictive ability of the T-lymphocyte proliferation regulator signature was validated by receiver operating characteristic curve analysis. Immune infiltration analysis revealed different immune statuses in both groups. CONCLUSIONS: We established a new T-lymphocyte proliferation regulator signature that can predict the prognosis of OSCC. The results of this study will contribute to studies of T-cell proliferation and the immune microenvironment in OSCC to improve prognosis and immunotherapeutic response.
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The characteristics and functional significance of disulfidptosis-related genes in head and neck squamous cell carcinoma.
Disulfidptosis is a newfound programmed cell death (PCD) mode characterized by disulfide stress. Nevertheless, the characteristics and functional significance of disulfidptosis-related genes in head and neck squamous cell carcinoma (HNSCC) are still largely unknown. In this study, several computer-aided bioinformatic analyses were performed. The Nonnegative Matrix Factorization (NMF) method classified The Cancer Genome Atlas (TCGA) patients into two clusters according to the expression of disulfidptosis-related genes. The relative compositions of cells in the tumor microenvironment (TME), mutant landscape, lasso regression analysis, and predicted clinical outcome were performed by analyzing bulk RNA-sequencing data. Besides, single-cell sequencing data (scRNA) was analyzed by Seurat, CopyKAT, and monocle2 to reveal the expression characteristics of disulfidptosis-related genes. Moreover, the spatial distribution characteristics of each cell subgroup in the section and the functional significance of cancer-associated fibroblasts (CAFs) were elucidated by STUtility, SpaCET, and SPATA2. Here, two clusters with different expression characteristics of disulfidptosis-related genes were identified. Cluster 1 (C1) patients had a worse prognosis and a higher proportion of stromal cells but lower effector T cell infiltration than cluster 2 (C2). A novel prognostic model was established and verified in our patient cohort. Additionally, diploid and inflammatory CAFs (iCAFs) showed higher disulfidptosis-related gene expression levels. Furthermore, the CCNC and CHMP1B expressions significantly changed following CAFs differentiation. Disulfidptosis-related genes exhibited extensive and differential spatial expression on tissue sections. Collectively, our study may contribute to revealing the function of disulfidptosis, and improve the expansion of knowledge of crosstalk between cancer cells and CAFs.