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Effect of radiotherapy on head and neck cancer tissues in patients receiving radiotherapy: a bioinformatics analysis-based study.
Radiotherapy is pivotal in treating head and neck cancers including nasopharyngeal, tongue, hypopharyngeal, larynx, maxillary sinus, parotid gland, and oral cancers. It holds the potential for curative effects and finds application in conjunction with chemotherapy, either as a radical method to preserve organ function or as an adjuvant postoperative treatment. We used bioinformatics analysis to investigate the effects of radiotherapy on head and neck cancer tissues in patients who had received radiotherapy. In this study, the expression and mutation profiles of The Cancer Genome Atlas-Head-Neck Squamous Cell Carcinoma were downloaded from the UCSC-Xena database, categorizing patients into two groups-those receiving radiotherapy and those not receiving radiotherapy. Subsequently, differential expression analysis and gene set enrichment analysis (GSEA) were performed. Following this, single-sample GSEA (ssGSEA) scores related to glucose and lipid metabolism were compared between the two groups. Additionally, immune cell infiltration analysis and single-cell verification were performed. Finally, the mutation profiles of the two groups were compared. The analyses revealed that patients receiving radiotherapy exhibited prolonged survival, enhanced apoptosis in head and neck cancer tissue, and diminished keratinocyte proliferation and migration. A comparison of ssGSEA scores related to glucose and lipid metabolism between the two groups indicated a reduction in glycolysis, tricarboxylic acid cycle activity, and fat synthesis in tissues treated with radiotherapy, suggesting that radiotherapy can effectively inhibit tumour cell energy metabolism. Analyses of immune cell infiltration and single-cell verification suggested decreased infiltration of immune cells post-radiotherapy in head and neck cancer tissues. A comparison of mutation profiles revealed a higher frequency of TP53, TTN, and CDKN2A mutations in patients receiving radiotherapy for head and neck cancer. In conclusion, the bioinformatics analyses delved into the effect of radiotherapy on patients with head and neck carcinoma. This study provides a theoretical framework elucidating the molecular mechanisms underlying radiotherapy's efficacy in treating head and neck cancer and presents scientific recommendations for drug therapy following radiotherapy.
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Contribution of MMP14-expressing cancer-associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer.
Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients (n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell-based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14+ cells among intratumoral CAFs (MMP14+ CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14+ CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14+ CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14+ CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target.
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NGEF is a potential prognostic biomarker and could serve as an indicator for immunotherapy and chemotherapy in lung adenocarcinoma.
BACKGROUND: Neuronal guanine nucleotide exchange factor (NGEF) plays a key role in several cancers; however, its role in lung adenocarcinoma (LUAD) remains unclear. The aim of this study was to evaluate the efficacy of NGEF as a prognostic biomarker and potential therapeutic target for LUAD. METHODS: NGEF expression data for multiple cancers and LUAD were downloaded from multiple databases. The high- and low-NGEF expression groups were constructed based on median NGEF expression in LUAD samples, and then performed Kaplan-Meier survival analysis. Differentially expressed genes (DEGs) from the two NGEF expression groups were screened and applied to construct a protein-protein interaction network. The primary pathways were obtained using gene set enrichment analysis. The associations between NGEF expression and clinical characteristics, immune infiltration, immune checkpoint inhibitors (ICIs), sensitivity to chemotherapy, and tumor mutation burden (TMB) were investigated using R. Levels of NGEF expression in the lung tissue was validated using single-cell RNA sequencing, quantitative polymerase chain reaction (qPCR), immunohistochemical staining, and western blot analysis. RESULTS: The expression of NGEF mRNA was upregulated in multiple cancers. mRNA and protein expression levels of NGEF were higher in patients with LUAD than in controls, as validated using qPCR and western blot. High NGEF expression was an independent prognostic factor for LUAD and was associated with advanced tumor stage, large tumor size, more lymph node metastasis, and worse overall survival (OS). A total of 182 overlapping DEGs were screened between The Cancer Genome Atlas and GSE31210, among which the top 20 hub genes were identified. NGEF expression was mainly enriched in the pathways of apoptosis, cell cycle, and DNA replication. Moreover, elevated NGEF expression were associated with a high fraction of activated memory CD4+ T cells and M0 macrophages; elevated expression levels of the ICIs: programmed cell death 1 and programmed cell death 1 ligand 1 expression; higher TMB; and better sensitivity to bortezomib, docetaxel, paclitaxel, and parthenolide, but less sensitivity to axitinib and metformin. CONCLUSION: NGEF expression is upregulated in LUAD and is significantly associated with tumor stages, OS probability, immune infiltration, immunotherapy response, and chemotherapy response. NGEF may be a potential diagnostic and prognostic biomarker and therapeutic target in LUAD.
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Promoting astrocyte-neuron triiodothyronine shuttling attenuates brain damage in neonatal hypoxic-ischemic encephalopathy.
BACKGROUND: Neonatal Hypoxic-Ischemic Encephalopathy (HIE) is a critical lifelong disabling neonatal disease with insufficient effective therapies. Signaling molecules derived from Astrocyte-Neuron Crosstalk have the potential to improve the prognosis, but relevant HIE research is limited. METHODS: We established hypoxic–ischemic brain damage (HIBD) in postnatal day 7 rat pups using the Rice–Vannucci model, and verified the injury both structurally and hemodynamically by histopathology and laser speckle contrast imaging. Whole-brain single-cell RNA sequencing was performed at P10, and proteomic profiling was conducted on astrocytes subjected to oxygen–glucose deprivation. We charted astrocyte diversity in situ using multiplex immunofluorescence. Thyroid hormones and signaling pathways were quantified by ELISA and Western blotting. Therapeutic efficacy was assessed by histopathology and the Morris water maze. RESULTS: A brain-wide single-cell transcriptomic atlas revealed a strong transcriptional coupling between astrocytes and neurons. Among astrocytes, we identified and functionally characterized a Dio2⁺Slc1a2⁺ subpopulation with metabolic and neuroprotective features, which was markedly depleted after HIBD. Pseudotime trajectories showed dynamic astrocyte state transitions over time, contextualizing the loss and reparative potential of the Dio2⁺ subpopulation. In vivo and in vitro, boosting astrocytic Dio2 or delivering exogenous Triiodothyronine(T3) enhanced neural repair and improved behavior across both early and long-term stages. CONCLUSIONS: We defined a previously unrecognized neuroprotective astrocyte subpopulation and revealed temporal heterogeneity in astrocytic inflammatory responses in HIE. We also identified a T3-mediated astrocyte–neuron crosstalk mechanism that mitigated HIBD, highlighting a tractable therapeutic avenue.
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Integrated transcriptomic and functional analyses identify PRR7 as a therapeutic target that associated with Wnt/β-catenin signaling and docetaxel resistance in prostate cancer.
BACKGROUND: Docetaxel resistance represents a major therapeutic challenge in advanced prostate cancer. Despite extensive studies on drug efflux, apoptosis, and metabolic adaptation, the specific cellular states and molecular determinants that sustain resistance remain poorly understood. METHODS: To delineate the cellular basis of chemoresistance, we integrated bulk RNA sequencing of docetaxel-resistant prostate cancer models with single-cell transcriptomic data from patient tumors. Resistance-associated gene signatures were projected onto a single-cell atlas to identify docetaxel-resistant associated cancer cells (DRACs). Candidate regulators were screened through cross-dataset analysis and validated using molecular, cellular, and organoid-based assays, with functional and signaling consequences evaluated across in vitro and in vivo systems. RESULTS: Single-cell mapping revealed a distinct epithelial cluster characterized by enrichment of resistance-related transcriptional programs and extensive communication with stromal cells. Integrative analyses identified PRR7 as a consistently upregulated gene within DRACs and resistant cell lines. PRR7 amplification and co-alteration with PI3K-AKT and Wnt pathway components were observed in clinical datasets. Functional inhibition of PRR7 suppressed β-catenin signaling, reduced cell viability, and downregulated stemness markers in docetaxel-resistant cells and patient-derived organoids. These results support a functional association between PRR7 and Wnt/β-catenin-related maintenance of resistance. CONCLUSION: The study defines DRACs as a transcriptionally distinct subpopulation sustaining docetaxel tolerance and identifies PRR7 as a regulatory hub connecting genomic alterations, Wnt/β-catenin activation, and stem-like phenotypes. These findings provide a framework for understanding chemoresistance in prostate cancer and suggest PRR7-centered signaling as a potential target for therapeutic intervention.
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Increased expression of tribbles homolog 3 predicts poor prognosis and correlates with tumor immunity in clear cell renal cell carcinoma: a bioinformatics study.
Tribbles homolog 3 (TRIB3), a pseudokinase that regulates multiple intracellular signaling pathways, has been reported to promote the growth of multiple tumors. However, its role in clear cell renal cell carcinoma (ccRCC) remains unelucidated. We evaluated the role of TRIB3 in ccRCC using publicly available data from The Cancer Genome Atlas and analyzed its relationship with the tumor microenvironment; moreover, we used gene knockout and overexpression techniques to detect the effects of TRIB3 on the biological behavior of ccRCC cells. RT-qPCR and western blotting were used to detect transfection efficiency, and the invasiveness of ccRCC cells was determined by Transwell migration assays. We found that TRIB3 overexpression was significantly associated with increased grade, stage, and distant metastasis, positively correlated with ccRCC invasiveness, and also an independent risk factor for overall survival (OS). In addition, 361 differentially expressed genes (DEGs) related to TRIB3 were identified. Functional enrichment analysis showed that DEGs were mainly enriched in humoral immune responses, collagen-containing extracellular matrix, and serine hydrolase activity. Immune landscape characterization revealed that TRIB3 expression was significantly and negatively associated with CD8+ T and hematopoietic stem cells, whereas it was positively associated with NK T and macrophage M1 cells. Single-cell sequencing showed that localization and binding targets of TRIB3 mainly involved monocytes/macrophages and CD4+ and CD8+ T cells. Overall, our study revealed that elevated TRIB3 expression represents a promising prognostic marker for ccRCC patients and may play a key role in tumor microenvironment modulation.
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Multi-omics comparison of periodontitis and peri-implantitis identifies plasma cell enrichment as a shared feature and a periodontitis-associated endothelial-plasma cell APP-CD74 axis.
OBJECTIVE: To define the shared and divergent immune architecture of periodontitis (PD) and peri-implantitis (PI) and to identify intercellular communication programs linked to plasma cell accumulation. METHODS: Differentially expressed genes (DEGs) in PD and PI versus healthy controls were identified from two bulk datasets (GSE223924, GSE106090); robust cross-dataset common DEGs underwent functional enrichment and protein-protein interaction analysis. A single-cell atlas (GSE171213) supported dual deconvolution (BisqueRNA, CIBERSORTx) and CellChat-based, plasma cell-centered communication inference. Key findings were independently validated in two additional periodontitis bulk cohorts (GSE10334, GSE16134) and an independent periodontitis single-cell dataset (GSE164241). Candidate ligand-receptor interactions were evaluated by spatial transcriptomics (GSE206621) and multiplex immunofluorescence in a rat periodontitis model. RESULTS: PI showed broader transcriptomic perturbation than PD (1,832 PI-specific and 820 PD-specific cross-validated DEGs). A total of 693 robust common DEGs with 99.0% directional concordance defined a shared inflammatory core enriched in cytokine signaling, B-cell activation, and osteoclast differentiation. Single-cell analysis resolved 15 cell populations and marked immune remodeling in periodontitis. Dual deconvolution identified plasma cell enrichment as the most reproducible infiltration feature across datasets and methods. CellChat revealed disease-associated remodeling of the plasma cell communication network, with endothelial cells as dominant senders and APP-CD74 as the strongest candidate incoming axis. Spatial transcriptomics showed a 14.43-fold increase in spot-level APP-CD74 co-enrichment in periodontitis-affected tissue, and multiplex immunofluorescence supported enhanced protein-level coupling between APP+CD31+ endothelial and CD74+CD138+ plasma cell domains. CONCLUSIONS: Plasma cell enrichment is the most robust shared immune feature of PD and PI. In periodontitis, convergent multi-omics and tissue-level evidence supports a candidate endothelial-plasma cell communication program centered on APP-CD74, suggesting that endothelial-plasma cell niche remodeling may sustain periodontal inflammation and inform host-modulatory strategies. Importantly, this axis was established only in periodontitis; its relevance to peri-implantitis remains inferential and will require direct single-cell and spatial validation in peri-implant tissue.
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Dynamic transcriptional immune landscape in response to NK-cell therapy combined with gemcitabine plus S-1 in advanced pancreatic cancer: a phase 1b/2 trial.
Despite advancements in several malignancies, the treatment atlas of natural killer (NK) cell therapy for pancreatic cancer remains inadequate, and the dynamic immune landscape underlying the various responses is still incompletely understood. This phase 1b/2 trial evaluated the safety and efficacy of allogeneic NK cell therapy combined with gemcitabine and S-1 as a first-line treatment for advanced pancreatic cancer (APC) and explored the dynamic responsive immune landscape (ChiCTR1900021764). The administration of 1 × 109 to 8 × 109 NK cells to 24 patients was well tolerated, with no graft-versus-host disease or dose-limiting toxicity. Among the 19 evaluable patients, the objective response rate was 31.6%, and the disease control rate was 73.7%. The median progression-free survival was 6.6 months, and the overall survival was 10.8 months. Further longitudinal single-cell RNA sequencing (scRNA-seq) of 19 paired-blood samples revealed an increased proportion of certain NK cell subsets (c4-ZEB2, c5-IL7, c6-IL15, c10-NCR3, and c11-TNFSF8) and T-cell subsets (CD8+ Teff and CD4+ Tem) in responders, characterized by increased expression of proinflammatory and effector molecules. Bulk T-cell receptor (TCR) Vβ repertoire sequencing of responders indicated potential T-cell clonal expansion, manifested as a greater abundance of large and hyperexpanded clonotypes. Our first-in-human trial demonstrated its safety and potentially preliminary efficacy, warranting further clinical evaluation. Multiomic profiling identified specific circulating NK and T-cell subsets potentially associated with clinical outcomes, providing novel insights into the dynamic transcriptional underpinnings of the immune landscape in response to NK cell-based therapy.
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TREM2 is associated with tumor immunity and implies poor prognosis in glioma.
Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in myeloid cells of the central nervous system (CNS), which mediate the immunological response in a variety of diseases. Uncertain is the function of TREM2 in glioma and tumor immune responses. In this research, the expression patterns of TREM2 in glioma were analyzed, along with its prognostic value and functional roles. TREM2 expression is increased in glioblastomas, gliomas with a mesenchymal subtype, gliomas with wild-type isocitrate dehydrogenase, and gliomas without 1p/19q deletion, all of which suggest the aggressiveness and poor prognosis of gliomas. Gene ontology, KEGG, and Gene set variation analyses indicated that TREM2 may serve as an immune response mediator. However, the function of T cells against tumor cells was negatively correlated with TREM2, suggesting that TREM2 may suppress tumor immunity. Further investigation demonstrated a correlation between TREM2 expression and immune checkpoint expression. CIBERSORT research revealed a link between a higher TREM2 expression level and the enrichment of tumor-associated macrophages, especially M2 subtype. Single-cell analysis and multiple immunohistochemical staining results showed that microglia and macrophage cells expressed TREM2. Immunofluorescent staining indicated that knocking down the expression of TREM2 would result in a decrease in M2 polarization. TREM2 was discovered to be an independent prognostic factor in glioma. In conclusion, our findings revealed that TREM2 was significantly expressed in microglia and macrophage cells and was intimately associated with the tumor immune microenvironment. Thus, it is expected that small-molecule medications targeting TREM2 or monoclonal antibodies would enhance the efficacy of glioma immunotherapy.
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Cross-Talk of Multiple Types of RNA Modification Regulators Uncovers the Tumor Microenvironment and Immune Infiltrates in Soft Tissue Sarcoma.
BACKGROUND: Soft-tissue sarcoma (STS) represents a rare and diverse cohort of solid tumors, and encompasses over 100 various histologic and molecular subtypes. In recent years, RNA modifications including m6A, m5C, m1A, and m7G have been demonstrated to regulate immune response and tumorigenesis. Nevertheless, the cross-talk among these RNA modification regulators and related effects upon the tumor microenvironment (TME), immune infiltrates, and immunotherapy in STS remain poorly understood. METHODS: In this study, we comprehensively investigated transcriptional and genetic alterations of 32 RNA modification regulators in STS patients from The Cancer Genome Atlas (TCGA) cohort and validated them in the Gene Expression Omnibus (GEO) cohort. Single-cell transcriptomes were introduced to identify regulators within specific cell types, with own sequencing data and RT-qPCR conducted for biological validation. Distinct regulator clusters and regulator gene subtypes were identified by using unsupervised consensus clustering analysis. We further built the regulator score model based on the prognostic regulator-related differentially expressed genes (DEGs), which could be used to quantitatively assess the risk for individual STS patients. The clinical and biological characteristics of different regulator score groups were further examined. RESULTS: A total of 455 patients with STS were included in this analysis. The network of 32 RNA modification regulators demonstrated significant correlations within multiple different RNA modification types. Distinct regulator clusters and regulator gene subtypes were characterized by markedly different prognoses and TME landscapes. The low regulator score group in the TCGA-SARC cohort was characterized by poor prognosis. The robustness of the scoring model was further confirmed by the external validation in GSE30929 and GSE17674. The regulator score was negatively correlated with CD4+ T cell, Th2 cell, and Treg cell recruitment and most immunotherapy-predicted pathways, and was also associated with immunotherapy efficacy. CONCLUSIONS: Overall, our study is the first to demonstrate the cross-talk of RNA modification regulators and the potential roles in TME and immune infiltrates in STS. The individualized assessment based on the regulator score model could facilitate and optimize personalized treatment.