Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 4 945
Страница 461 из 495-
Cutaneous T cell lymphoma atlas reveals malignant TH2 cells supported by a B cell-rich tumor microenvironment.
Cutaneous T cell lymphoma (CTCL) is a potentially fatal clonal malignancy of T cells primarily affecting the skin. The most common form of CTCL, mycosis fungoides, can be difficult to diagnose, resulting in treatment delay. We performed single-cell and spatial transcriptomics analysis of skin from patients with mycosis fungoides-type CTCL and an integrated comparative analysis with human skin cell atlas datasets from healthy and inflamed skin. We revealed the co-optation of T helper 2 (TH2) cell-immune gene programs by malignant CTCL cells and modeling of the tumor microenvironment to support their survival. We identified MHC-II+ fibroblasts and dendritic cells that can maintain TH2 cell-like tumor cells. CTCL tumor cells are spatially associated with B cells, forming tertiary lymphoid structure-like aggregates. Finally, we validated the enrichment of B cells in CTCL and its association with disease progression across three independent patient cohorts. Our findings provide diagnostic aids, potential biomarkers for disease staging and therapeutic strategies for CTCL.
-
Bioinformatics analysis of immune infiltrates and tripartite motif (TRIM) family genes in hepatocellular carcinoma.
BACKGROUND: The tripartite motif (TRIM) family are important members of the Gene-finger-containing E3 ubiquitin-conjugating enzyme and are involved in the progression of hepatocellular carcinoma (HCC). Previous studies have largely focused on gene expression and molecular pathways, while the underlying role of the TRIM family in the tumor immune microenvironment (TIME) remains poorly understood. METHODS: We systematically explored the correlations of prominent TRIM genes with immune checkpoints and immune infiltrates in 231 HCC samples [International Cancer Genome Consortium (ICGC) cohort (n=231); The Cancer Genome Atlas (TCGA) cohort (n=370)]. A prognostic risk model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analysis in the ICGC cohort. Kaplan-Meier curves based on the overall survival (OS) were used to assess differences in survival between clusters. We utilized gene set variation analysis (GSVA) to characterize the differences in biological functions. Based on univariate and multivariate Cox progression analysis, we developed a risk score signature and verified its reliability and validity. The Tumor Immune Single-cell Hub (TISCH) single-cell database was employed to evaluate the correlation of TRIM genes with the tumor microenvironment. RESULTS: Cluster 1 was preferentially associated with a favorable prognosis (P<0.001). The amino acid, fatty acid, and drug metabolism pathways were significantly enriched in cluster 2. A prognosis risk score project was established and evaluated based on the 9 independent prognostic genes (all P<0.05). The immune score and stromal scores of patients with low-risk scores were greater than those of patients with high-risk scores (all P<0.001). However, patients with a high-risk score exhibited lower responses to immune check-point inhibitors (ICIs), sorafenib, and transarterial chemoembolization (TACE) treatment (all P<0.05). Consistently, TRIM genes showed the same influence in the external TCGA cohort. TRIM gene-based signatures were implicated in TIME and their copy-number alterations dynamically impacted the abundance of tumor-infiltrating immune cells. CONCLUSIONS: Our findings revealed that MID1, TRIM5, TRIM22, TRIM28, TRIM 31, TRIM37, TRIM38, TRIM47, and TRIM74 could serve as efficient prognostic biomarkers and therapeutic targets in HCC. The identified TRIM gene-based signatures could serve as important TIME mediators in HCC, potentially increasing immune treatment efficacy.
-
FAT1 as a tumor mutation burden specific gene affects the immunotherapy effect in head and neck squamous cell cancer.
BACKGROUND: Response to immunotherapy is the main challenge of head and neck squamous cancer (HNSCC) treatment. Previous studies have indicated that tumor mutational burden (TMB) is associated with prognosis, but it is not always a precise index. Hence, investigating specific genetic mutations and tumor microenvironment (TME) changes in TMB-high patients is essential for precision therapy of HNSCC. METHODS: A total of 33 HNSCC patients were enrolled in this study. We calculated the TMB score based on next-generation sequencing (NGS) sequencing and grouped these patients based on TMB score. Then, we examined the immune microenvironment of HNSCC using assessments of the bulk transcriptome and the single-cell RNA sequence (scRNA-seq) focusing on the molecular nature of TMB and mutations in HNSCC from our cohort. The association of the mutation pattern and TMB was analyzed in The Cancer Genome Atlas (TCGA) and validated by our cohort. RESULTS: 33 HNSCC patients were divided into three groups (TMB-low, -medium, and -high) based on TMB score. In the result of 520-gene panel sequencing data, we found that FAT1 and LRP1B mutations were highly prevalent in TMB-high patients. FAT1 mutations are associated with resistance to immunotherapy in HNSCC patients. This involves many metabolism-related pathways like RERE, AIRE, HOMER1, etc. In the scRNA-seq data, regulatory T cells (Tregs), monocytes, and DCs were found mainly enriched in TMB-high samples. CONCLUSION: Our analysis unraveled the FAT1 gene as an assistant predictor when we use TMB as a biomarker of drug resistance in HNSCC. Tregs, monocytes, and dendritic cells (DCs) were found mainly enriched in TMB-high samples.
-
Integrative single-cell and spatial transcriptomic analysis reveals that ATG13 enriched in cancer-associated fibroblasts is associated with the suppression of ferroptosis in colorectal cancer.
BACKGROUND: Colorectal cancer (CRC) progression and metastasis are primarily driven by dynamic changes within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) exhibit significant heterogeneity within the TME and play a crucial role in regulating ferroptosis. Therefore, identifying novel ferroptosis-related biomarkers associated with CAFs could contribute to the development of personalized therapeutic strategies for cancer. METHODS: This study integrates single-cell sequencing data from 64 CRC samples and uses hierarchical clustering to identify cancer-associated fibroblast (CAF) subpopulations. We then combined spatial transcriptomics, hdWGCNA, CellChat, and Monocle analyses to characterize CAF subgroups. Single-cell and spatial transcriptomic data were integrated with Seurat to build a comprehensive spatial atlas. Multiplex immunohistochemical staining was used to analyze the spatial relationships of key genes with CAFs. Functional validation of these genes was performed with molecular docking, qPCR, Western blot, and both cellular and animal experiments. RESULTS: Single-cell data analysis identified five distinct CAF subpopulations, among which inflammatory cancer-associated fibroblasts (iCAFs) were significantly associated with the ferroptosis pathway and closely correlated with the proliferation and metastasis of malignant epithelial cells (p = 0.87). WGCNA revealed that the iCAFs-M10 module exhibited the strongest correlation with the expression of ferroptosis-related genes (cor = 0.6796). Further investigation identified ATG13 as a key hub gene, highly expressed in tumor tissues and significantly associated with poor patient prognosis. Spatial transcriptomics and multiplex immunohistochemistry (mIHC) results demonstrated that ATG13 was highly expressed in CAFs and co-localized with CAFs markers, such as α-SMA and Vimentin. In vitro and in vivo functional assays confirmed that ATG13 knockdown effectively inhibited the proliferation, migration, and invasion of colorectal cancer cells. Additionally, ferroptosis was induced upon ATG13 silencing, as evidenced by increased levels of GPX4, SLC7A11, ACSL4, MDA, Fe2⁺, GSH, and lipid peroxidation. In conclusion, this study reveals that ATG13, highly expressed in iCAFs, is associated with ferroptosis suppression in CRC, suggesting a potential CAF-tumor cell crosstalk axis that warrants further mechanistic investigation, thereby promoting the malignant progression of colorectal cancer. These findings provide potential targets for therapeutic strategies aimed at targeting the CAFs-ferroptosis axis. CONCLUSION: This study identifies the iCAFs subpopulation as playing a key role in regulating ferroptosis in CRC, with ATG13 acting as a negative regulator of ferroptosis that promotes tumor progression. These findings provide new insights and potential targets for understanding the mechanisms of ferroptosis in CRC and for the development of targeted therapies.
-
A Single-cell Atlas of Developing Mouse Palates Reveals Cellular and Molecular Transitions in Periderm Cell Fate.
Cleft palate is one of the most common congenital craniofacial disorders that affects children's appearance and oral functions. Investigating the transcriptomes during palatogenesis is crucial for understanding the etiology of this disorder and facilitating prenatal molecular diagnosis. However, there is limited knowledge about the single-cell differentiation dynamics during mid-palatogenesis and late-palatogenesis, specifically regarding the subpopulations and developmental trajectories of periderm, a rare but critical cell population. Here, we explored the single-cell landscape of mouse developing palates from embryonic day (E) 10.5 to E16.5. We systematically depicted the single-cell transcriptomes of mesenchymal and epithelial cells during palatogenesis, including subpopulations and differentiation dynamics. Additionally, we identified four subclusters of palatal periderm and constructed two distinct trajectories of cell fates for periderm cells. Our findings reveal that claudin-family coding genes and Arhgap29 play a role in the non-stick function of the periderm before the palatal shelves contact, and Pitx2 mediates the adhesion of periderm during the contact of opposing palatal shelves. Furthermore, we demonstrate that epithelial-mesenchymal transition (EMT), apoptosis, and migration collectively contribute to the degeneration of periderm cells in the medial epithelial seam. Taken together, our study suggests a novel model of periderm development during palatogenesis and delineates the cellular and molecular transitions in periderm cell determination.
-
The significance of immunogenic cell death related prognostic gene markers in colorectal cancer prognosis and antitumor immunity.
Immunogenic cell death (ICD) plays a critical role in the host’s antitumor immune response, and its dysregulation is linked to poor prognosis in colorectal cancer (CRC). Identifying ICD-related genes and developing prognostic models can enhance the prediction of patient outcomes and facilitate personalized treatments. Utilizing data from CRC patients in the Cancer Genome Atlas, we employed weighted gene co-expression network analysis, LASSO regression analysis, and multivariate Cox regression screening to identify immunogenic cell death-related prognostic genes (IPGs) in CRC patients. An IPGs scoring system was constructed, allowing for the stratification of patients into high-risk and low-risk groups based on the best cutoff ICD-RiskScore, with the Gene Expression Omnibus dataset serving as a validation cohort. We then examined the correlations between the high-risk and low-risk groups concerning clinicopathological features, immune infiltration, immunotherapy responses, and tumor mutational burden. Additionally, we analyzed the cellular landscape and cell-cell interactions in colorectal cancer at a single-cell resolution. A prognostic model comprising 12 immune-related prognostic genes (IPGs)—CAV2, NOXA1, TGFB2, WRNIP1, CCL22, ICAM2, APOBEC3F, COTL1, CTSD, IDO1, NFATC1, and RUNX3—was established, demonstrating a high area under the curve value in survival analysis, which indicates robust predictive performance. In comparison to the low-risk group, the high-risk group exhibited lower survival rates, higher mutation rates of genes, and was associated with more advanced tumor stages. Single-sample gene set enrichment analysis revealed that the low-risk group possessed a stronger immune surveillance function. Additionally, single-cell analysis uncovered a lower abundance of immune cells and an increased proportion of epithelial cells within tumor samples. The frequency of interactions among epithelial cells, endothelial cells, and fibroblasts was found to be elevated in tumor samples. Subsequently, validation of the prognostic genes revealed that COTL1 expression was significantly elevated in CRC tissues compared to adjacent normal tissues (P < 0.05). This study presents a prognostic model for colorectal cancer that integrates 12 immune-related genes. The model holds potential clinical value in predicting patient prognosis and guiding personalized treatment strategies. These findings also provide insights into the molecular mechanisms of immune cell dynamics in colorectal cancer and highlight potential therapeutic targets.
-
Comprehensive analysis the prognostic and immune characteristics of mitochondrial transport-related gene SFXN1 in lung adenocarcinoma.
BACKGROUND: Mitochondria, which serve as the fundamental organelle for cellular energy and metabolism, are closely linked to the growth and survival of cancer cells. This study aims to identify and assess Sideroflexin1 (SFXN1), an unprecedented mitochondrial gene, as a potential prognostic biomarker for lung adenocarcinoma (LUAD). METHODS: The mRNA and protein levels of SFXN1 were investigated based on the Cancer Genome Atlas (TCGA) LUAD dataset, and then validated by real-time quantitative PCR, Western Blotting and immunohistochemistry from our clinical samples. The clinical correlation and prognostic value were evaluated by the TCGA cohort and verified via our clinical dataset (n = 90). The somatic mutation, drug sensitivity data, immune cell infiltration and single-cell RNA sequencing data of SFXN1 were analyzed through public databases. RESULTS: SFXN1 was markedly upregulated at both mRNA and protein levels in LUAD, and high expression of SFXN1 were correlated with larger tumor size, positive lymph node metastasis, and advanced clinical stage. Furthermore, SFXN1 upregulation was significantly associated with poor clinical prognosis. SFXN1 co-expressed genes were also analyzed, which were mainly involved in the cell cycle, central carbon metabolism, DNA repair, and the HIF-1α signaling pathway. Additionally, SFXN1 expression correlated with the expression of multiple immunomodulators, which act to regulate the tumor immune microenvironment. Results also demonstrated an association between SFXN1 expression and increased immune cell infiltration, such as activated CD8 + T cells, natural killer cells (NKs), activated dendritic cells (DCs), and macrophages. LUAD patients with high SFXN1 expression exhibited heightened sensitivity to multiple chemotherapies and targeted drugs and predicted a poor response to immunotherapy. SFXN1 represented an independent prognostic marker for LUAD patients with an improved prognostic value for overall survival when combined with clinical stage information. CONCLUSIONS: SFXN1 is frequently upregulated in LUAD and has a significant impact on the tumor immune environment. Our study uncovers the potential of SFXN1 as a prognostic biomarker and as a novel target for intervention in LUAD.
-
Comprehensive single-cell atlas of colorectal neuroendocrine tumors with liver metastases: unraveling tumor microenvironment heterogeneity between primary lesions and metastases.
BACKGROUND: Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients. METHODS: We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence. RESULTS: Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort. CONCLUSION: Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.
-
Identification of a novel prognostic marker ADGRG6 in pancreatic adenocarcinoma: multi-omics analysis and experimental validation.
BACKGROUND: Pancreatic adenocarcinoma (PAAD) ranks among the most lethal malignancies worldwide. Current treatment options have limited efficacy, underscoring the need for new therapeutic targets. METHODS: This study employed a multi-omics analytical framework to delve into the expression profiles and prognostic implications of ADGRG6 within the pan-cancer dataset of The Cancer Genome Atlas (TCGA) database, highlighting the prognostic value and potential carcinogenic role of ADGRG6 in PAAD, which was further validated using data from multiple PAAD cohorts in the Gene Expression Omnibus (GEO) database. To assess the role of ADGRG6 in the tumor microenvironment of PAAD, we evaluated immune infiltration using CIBERSORT, ssGSEA, xCell and Tracking Tumor Immunophenotype (TIP), and utilized single-cell sequencing data to explore cell-cell interactions. Further cellular and animal experiments, such as colony formation assay, transwell assay, western blot, real-time PCR, and tumor xenograft experiments, were used to investigate the effect of ADGRG6 on the proliferation, metastatic potential and immune marker expression of PAAD and the underlying mechanisms. RESULTS: ADGRG6 emerged as a potential prognostic biomarker and a therapeutic target for PAAD, which was further corroborated by data extracted from multiple PAAD cohorts archived in the GEO database. Single-cell sequencing and immune infiltration analyses predicted the positive correlation of ADGRG6 with the infiltration of immune cells and with the interaction between malignant cells and fibroblasts/macrophages within the PAAD microenvironment. In vitro cell assays demonstrated that ADGRG6 promoted the proliferation, metastatic potential and immune marker expression of PAAD cells by increasing protein level of mutated p53 (mutp53), which activated a spectrum of gain-of-functions to promote cancer progression via the EGFR, AMPK and NF-κB signaling cascades. Furthermore, subcutaneous xenograft experiments in mice demonstrated that ADGRG6 knockdown substantially suppressed the growth of engrafted PAAD tumors. CONCLUSIONS: ADGRG6 may serve as a novel prognostic marker and a therapeutic targets for PAAD, playing a crucial role in the proliferation, metastasis, and immune marker regulation of PAAD through elevating protein level of mutated p53.
-
PRAME Expression in Melanoma is Negatively Regulated by TET2-Mediated DNA Hydroxymethylation.
Preferentially expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of The Cancer Genome Atlas and Genotype-Tissue Expression databases confirmed a negative relationship between TET2 and PRAME messenger RNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared with nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis.