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PubMed2025

Epstein-Barr Virus-Associated Gastric Cancer: A Histopathologic Study With Comprehensive Molecular Profiling.

A subset of gastric cancers (GCs) is linked to Epstein-Barr virus (EBV) infection. This study aims to characterize the histopathological and molecular features of EBV-associated GCs (EBVaGCs), focusing on predictive biomarkers and genomic and transcriptomic analysis. A total of 35 primary EBVaGCs were considered. The presence of EBV was confirmed with in situ hybridization. Immunohistochemical analyses for HER2, PD-L1, claudin 18.2, and mismatch repair proteins were performed. Genomic and transcriptomic profiles were assessed using AmoyDx Master Panel, which can identify single-nucleotide variants, InDels, and copy number variations on 571 hot genes, as well as microsatellite status, tumor molecular burden, and homologous recombination deficiency at the DNA level; however, at the RNA level, it identifies rearrangements/fusions in 45 genes and also quantifies the expression of 2396 cancer-related transcripts. The following histotypes were identified: carcinoma with lymphoid stroma (CLS; 69%), tubular (20%), and mixed (11%). Most cases were associated with atrophic gastritis (71%), and only 11% with dysplasia. The vast majority (94%) of EBVaGCs expressed EBV-encoded RNA in all tumor cells. Mismatch repair deficiency and HER2 overexpression were each observed in 6% of cases, whereas all tumors had a PD-L1-combined positive score ≥10. Sixty-six percent of cases showed moderate/strong claudin 18.2 expression in ≥75% of cancer cells. The most frequently altered genes were PIK3CA (41%) and ARID1A (17%). Transcriptomic analysis revealed substantial differential gene expression between EBVaGCs and EBV-negative controls, with upregulation of genes involved in antigen presentation, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction in EBVaGCs. Within EBVaGC, CLS showed higher expression of immune-related transcripts and higher PD-L1 expression than other histotypes. This study establishes EBVaGC as a distinct molecular class, with a distinctive profile of genomic alterations and expression of predictive biomarkers, and also with a unique immune microenvironment with enhanced cytotoxic activity. The findings highlight EBV's role in early tumor development and EBVaG-CLS as a distinct subgroup within EBVaGC, characterized by unique morphologic features and a pronounced immune activation profile.

Humans↗

PubMed2026

Activation of mTOR pathway by human cytomegalovirus promoting host ribosomal protein expression by coordinated transcriptional and translational controls.

Human cytomegalovirus (HCMV) profoundly reprograms host transcription and RNA metabolism, yet its impact on transcription start site (TSS) regulation of host genes remains poorly understood. Here, we employed NanoCap Analysis of Gene Expression sequencing (NanoCAGE-seq) to investigate HCMV-driven changes in alternative TSS usage across the host transcriptome. We identified widespread TSS switching, with ribosomal protein genes (RPGs) emerging as a highly enriched category. Alternative TSS usage produced isoforms with distinct 5'untranslated regions (UTRs), thereby altering cis-regulatory elements that shape translational efficiency. Integrative transcriptomic and proteomic analyses revealed a paradoxical accumulation of RPG proteins despite transcriptional downregulation during infection. Using 5' Rapid Amplification of cDNA Ends (5'RACE), we characterized four RPGs of RPL4, RPS11, RPS23, and RPS24 that generated 5'UTR variants through alternative TSS usage. Notably, isoforms containing a 5'terminal oligopyrimidine (5'TOP) motif were significantly enriched, correlating with mTOR activation induced by HCMV. Functional assays with bicistronic reporter constructs in HEK293 cells and infection models in human embryonic lung fibroblasts demonstrated that the RPL4 5'TOP isoform exhibited enhanced mTORC1-driven translation compared with non-5'TOP counterparts. Importantly, RPL4 upregulation facilitated viral protein synthesis and boosted production of infectious virions. Together, our findings reveal that dynamic TSS switching of RPGs provides a simple, yet effective, mechanism for fine-tuning mTORC1-responsive translation. By co-opting host transcriptional and translational programs, HCMV enhances ribosome function to optimize the cellular environment for productive viral replication.

Humans↗

PubMed2025

Growth-limiting drought increases sensitivity of Asian rice (Oryza sativa) leaves to heat shock through physiological and spatially distinct transcriptomic responses.

Growth-limiting droughts (GLD) impair tissue expansion and delay developmental transitions but are often not considered as stressors, as many physiological traits are only slightly altered relative to well-watered counterparts. Concurrently, cell size, biochemical makeup, and transcriptome profiles vary along the leaf blade in accordance with the partitioning of distinct functions to spatially defined regions of the leaf. This suggests that because different parts of the leaf have underlying differences in their transcriptome profiles, they might respond to GLD in distinctive ways. Moreover, how antagonistic stressors influence physiology and gene expression in different zones of leaves is an open question. In this study, we profiled growth, anatomy, and gas exchange in Asian rice (Oryza sativa) leaves developed in well-watered and GLD conditions, with or without a secondary heat shock. We dissected leaves into seven equal-length segments for transcriptome analysis in these conditions. We hypothesized that GLD would make the leaves more sensitive to heat shock and would disrupt the underlying heterogeneity of the leaf transcriptome. GLD plants were more strongly affected by heat shock with respect to gas exchange and the number and types of genes that were differentially expressed and that these differences varied along the leaf blade. We developed an eFP browser tool with these data to facilitate exploration and hypothesis testing. These findings show that even mild drought treatments are sufficient to impact responses to antagonistic stressors and that substantial within-organ variance exists with respect to stress responses.

Oryza↗

PubMed2024

Bioinformatic approaches for accurate assessment of A-to-I editing in complete transcriptomes.

A-to-I RNA editing is an RNA modification that alters the RNA sequence relative to the its genomic blueprint. It is catalyzed by double-stranded RNA-specific adenosine deaminase (ADAR) enzymes, and contributes to the complexity and diversification of the proteome. Advancement in the study of A-to-I RNA editing has been facilitated by computational approaches for accurate mapping and quantification of A-to-I RNA editing based on sequencing data. In this chapter we review some of the main computational approaches currently used, describe potential hurdles, challenges and pitfalls, and discuss possible ways to mitigate them.

RNA Editing↗

PubMed2026

Pan-genome characterization of the maize 4CL gene family and its dynamic responses to abiotic stress.

1.Pan-genome analysis across 26 maize inbred lines identified 13 Zm4CL genes (nine core and four near-core) classified into three evolutionary clades.2.Structural variations (SVs) are significantly associated with the expression and altered conserved protein domains of key Zm4CL genes.3.Zm4CL genes exhibit distinct tissue-specific expression patterns and dynamic enzymatic and transcriptional responses to stresses, particularly cold and drought.4-Coumarate:CoA ligase (4CL) is a key enzyme in the phenylpropanoid pathway and plays important roles in plant growth, development, and responses to environmental stresses. However, a comprehensive pan-genome analysis of the 4CL gene family in maize is still lacking. In this study, 13 Zm4CL genes were identified from a maize pan-genome comprising 26 diverse inbred lines, including nine core genes and four near-core genes. Phylogenetic analysis classified these genes into three evolutionary clades, while Ka/Ks analysis indicated that most members have been maintained under purifying selection, although several genes exhibited greater evolutionary divergence and relatively relaxed evolutionary constraints. Structural variation (SV) analysis revealed significant associations between SVs and the expression of Zm4CL2 and Zm4CL3, while sequence comparisons suggested that SVs were also associated with alterations in conserved protein domains in some genotypes. Transcriptome analyses revealed distinct tissue-specific expression patterns and diverse transcriptional responses to abiotic and biotic stresses. Enzyme activity assays showed that cold stress significantly increased 4CL activity at 12 h, whereas heat, salt, and alkali stresses caused an initial decrease followed by recovery, while drought had no significant effect. Time-course RT-qPCR further validated dynamic expression changes of representative Zm4CL genes under cold and drought stresses. Overall, this study provides a comprehensive pan-genome framework for understanding the evolutionary conservation, regulatory diversification, and stress-responsive characteristics of the maize Zm4CL gene family, providing valuable resources for future functional studies and the genetic improvement of stress tolerance in maize.

Zea mays↗

PubMed2026

Integrative Genomic Profiling of Newly Diagnosed Prostate Cancers Progressing on Surveillance.

OBJECTIVE: To identify molecular features associated with earlier progression to definitive therapy amongst patients with localized prostate cancer (PCa) managed on active surveillance (AS). METHODS: We performed a retrospective pilot study of 7 patients with low- to intermediate-risk PCa undergoing serial multiparametric MRI (mpMRI)-targeted biopsies of the same lesion while on AS, who all proceeded to definitive therapy. Time-to-treatment (TTT) was defined as years from first biopsy on AS to definitive therapy. Laser-capture microdissection was used to separate tumor epithelium, benign glands, high-grade prostatic intraepithelial neoplasia, and stroma in each biopsy specimen. DNA from the tumor and matched benign tissue underwent whole-exome sequencing, and RNA from all compartments underwent whole-transcriptome sequencing. Somatic mutations and copy-number alterations were compared across serial biopsies and used to reconstruct phylogenies and quantify clonal complexity. RESULTS: Tumors exhibited substantial intratumoral heterogeneity, and in 3 of 6 paired cases, serial mpMRI-targeted biopsies showed discordant somatic profiles consistent with sampling distinct major clones over time. By contrast, no single gene-level alteration, and few large-scale chromosomal events, were associated with TTT. High clonal complexity, defined as ≥3 subclones, was associated with significantly shorter TTT than low complexity (median 1.9 vs 7.2 years; P = .0082). Exploratory pathway analyses of individual tissue components suggested TTT-associated differences in inflammatory signaling and stromal-epithelial cross-talk. CONCLUSION: In this small, hypothesis-generating cohort, clonal complexity was more closely associated with earlier definitive therapy than individual genomic alterations. Larger prospective studies are needed to validate whether multiomic measures of clonal architecture can improve AS risk stratification.

Humans↗

PubMed2025

Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.

We have investigated changes in chromosome conformation, nuclear organization, and transcription during differentiation and maturation of control and mutant motor neurons harboring hexanucleotide expansions in the C9orf72 gene that cause amyotrophic lateral sclerosis (ALS). Using an in vitro reprogramming, differentiation and neural maturation protocol, we obtained highly purified populations of post-mitotic motor neurons for both normal and diseased cells. As expected, as fibroblasts are reprogrammed into iPSCs, and as iPSCs differentiate into motor neurons, chromatin accessibility, chromosome conformation, and nuclear organization change along with large-scale alterations in transcriptional profiles. We find that the transcriptome changes extensively during the first three weeks of post-mitotic neuronal maturation, with thousands of genes changing expression, but then is relatively stable for the next three weeks. In contrast, chromosome conformation and nuclear organization continue to change over the entire 6-week maturation period: chromosome territoriality increases, long-range interactions along chromosomes decrease, compartmentalization strength increases, and centromeres and telomeres increasingly cluster. In motor neurons derived from ALS patients such changes in chromosome conformation were much reduced. Chromatin accessibility changes also showed delayed maturation. The transcriptome in these cells matured relatively normally but with notable changes in expression of genes involved in lipid, sterol and mitochondrial function. We conclude that neural maturation is associated with large scale post-mitotic changes in gene expression, chromosome conformation and nuclear organization, and that these processes are defective in motor neurons derived from ALS patients carrying C9orf72 hexanucleotide repeat expansions.

Journal Article↗

PubMed2024

A Strong Dysregulated Myeloid Component in the Epigenetic Landscape of Systemic Sclerosis: An Integrated DNA Methylome and Transcriptome Analysis.

OBJECTIVE: Nongenetic factors influence systemic sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study. METHODS: We analyzed DNA methylation data from whole-blood samples in 179 patients with SSc and 241 unaffected individuals to identify differentially methylated positions (DMPs) with a false discovery rate (FDR) <0.05. These results were further integrated with RNA sequencing data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels. RESULTS: This analysis yielded 525 DMPs enriched in immune-related pathways, with leukocyte cell-cell adhesion being the most significant (FDR = 4.91 × 10-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach, we observed an enrichment of neutrophil-related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein transcription factor family in SSc, which is crucial in the myeloid lineage development. CONCLUSION: Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.

Humans↗

PubMed2025

Genomic and Transcriptomic Landscape of Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma: A Multicenter Study.

Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare indolent malignant neoplasm, which occurs almost exclusively in the liver or spleen and may arise from a common EBV-infected mesenchymal cell that differentiates along the follicular or fibroblastic dendritic cell pathway. Despite its rarity, it presents a pressing need for an improved understanding of its genetic underpinnings and potential treatment strategies for recurrent or disseminated cases. To address this, we conducted comprehensive whole-exome sequencing and transcriptome sequencing (mRNA-seq) analyses on 31 and 6 cases of EBV+ IFDCS, respectively, collected from multiple centers in China. We also compared the genetic features of EBV+ IFDCS with those of other EBV-associated malignancies. Our analyses revealed a relatively high somatic mutation rate and widespread copy number variations affecting the major histocompatibility complex-I/II in EBV+ IFDCS. Integrated mutational profiling identified key signaling pathways involved in epigenetic regulation, NF-κB signaling, RTK/RAS/PI(3)K, and the Hippo pathway. Furthermore, we identified several frequently altered genes that could serve as potential therapeutic targets in EBV+ IFDCS. Transcriptomic analysis unveiled significant upregulation of pathways related to virus infection, immune responses, and multiple immune checkpoint genes in EBV+ IFDCS. Comparative analysis demonstrated clear genetic distinctions between EBV+ IFDCS and other EBV-associated tumors. In conclusion, our study provides comprehensive insights into the unique genomic and transcriptomic landscape of EBV+ IFDCS. We have identified multiple genetic alterations that likely contribute to the development and progression of this malignancy. Our results suggest that targeted therapy and immune checkpoint inhibitors may hold promise as potential therapeutic approaches for patients with recurrent or disseminated EBV+ IFDCS.

Humans↗

PubMed2026

Estrone disrupts early reproductive development in juvenile male Siniperca chuatsi and is associated with brain and gonadal responses.

Whether estrone (E1)-associated disruption of early reproductive development in fish is accompanied by brain responses in addition to direct gonadal effects remains unclear. Here, juvenile Siniperca chuatsi, a non-model but economically important freshwater species, were exposed for 60 d to 0, 0.01, 0.1, and 1.0 μg/L E1, spanning environmentally reported and elevated concentrations. By integrating waterborne concentration monitoring, histopathology, transcriptomics, and quantitative real-time PCR (qPCR) validation, we evaluated E1-associated changes in brain and gonadal tissues during early reproductive development. Waterborne E1 concentrations remained generally stable throughout the exposure period. At the highest tested concentration (1.0 μg/L), E1 caused neuronal vacuolation and pyknosis in the hypothalamic region and induced distinct ovarian-like structures in the gonads of genetic males. In the brain, cyp19a1, crhr1, and adcy2a were significantly upregulated, whereas egr1 was significantly downregulated, indicating transcriptional changes in genes associated with local estrogen conversion, stress-response/cAMP signaling, and neuronal activity-related regulation within a broader injury/stress-response background. In the gonad, RNA-seq analysis showed significant downregulation of star2, hsd3b1, cyp17a1, and cyp11b and significant upregulation of hsd17b1, suggesting alterations in steroidogenesis-related gene expression at the transcriptomic level. qPCR analysis of selected gonadal candidate genes showed expression directions generally consistent with the RNA-seq results, and these molecular patterns were consistent with the feminized histological phenotype. Together, these results indicate that E1 can disrupt early reproductive development in juvenile S. chuatsi and support a cautious working model in which E1 exposure is accompanied by concurrent brain and gonadal responses. This study provides new evidence for understanding the toxic effects and ecological risk implications of natural estrogen E1 during early fish development.

Animals↗

PubMed2026

Immune subtyping of colorectal adenoma identifies a subtype with activated adaptive immunity ahead of progressing to cancer.

BACKGROUND: Colorectal adenomas (CRA) represent precursor lesions with varying risks of malignant transformation. However, molecular subtyping, particularly immune-related classification, remains underexplored in adenomas. This study aims to characterize the immune landscape of CRA through immune subtyping and evaluate its association with cancer progression, gene expression signatures, and functional pathways. METHODS: We conducted a retrospective analysis of transcriptomic data from multiple cohorts of CRA samples. Immune subtypes were identified using non-negative matrix factorization (NMF) based on immune-related genes. Diverse deconvolution algorithms were used to estimate immune cell infiltration. The immune status alteration in premalignant lesion was further consolidated by single-cell transcriptome data. Differential gene expression analysis was performed between subtypes, followed by functional enrichment analyses (Gene Ontology [GO] and Kyoto Encyclopedia of Genes and Genomes [KEGG]). RESULTS: Two distinct immune subtypes were identified: an immune-enriched subtype characterized by high lymphocyte infiltration and elevated expression of immune-related genes, and an immune-deficient subtype with suppressed immune activity. Differential expression analysis revealed significant upregulation of immune response genes (e.g., CD4, CD86, HLA-DRA) in the immune-enriched subtype. GO and KEGG analyses highlighted enrichments in leukocyte transendothelial migration, chemokine signaling, and antigen processing and presentation pathways. Single-cell result revealed an early occurrence of TIGIT activation and exhausted CD8 T cell features in adenoma when compared to normal tissue. CONCLUSION: This study delineates distinct immune subtypes within CRAs. The immune-enriched subtype demonstrates activated adaptive immunity and may reflect a higher potential for immune surveillance, while the immune-deficient subtype exhibits stromal features suggestive of progressive transformation. These findings provide insights into early immune microenvironment alterations and may inform strategies for risk stratification and immunoprevention in colorectal carcinogenesis.

Colorectal adenoma↗

PubMed2026

Comprehensive transcriptomics and proteomics analysis of neointima formation in human saphenous vein: implications for bypass graft disease.

Human saphenous veins (SVs) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima formation. Little is known, however, regarding the cellular, transcriptomic, and proteomic dynamics of neointima formation in human veins. Here, we performed transcriptomics and proteomics analysis in an ex vivo tissue culture model of neointima formation in human SVs procured for CABG surgery. Histological examination demonstrated significant elastin degradation and neointima formation (indicated by increased neointima area and neointima-to-media ratio) in SVs subjected to tissue culture. Analysis of data from 72 patients suggests that the progression of SV remodeling and neointima formation differs according to sex and body mass index, which is negatively associated with neointima formation in males only. RNA sequencing demonstrated upregulation of proinflammatory and proliferation-related genes during neointima formation and identified novel processes, including increased cellular stress and DNA damage responses, reflecting tissue trauma associated with vein harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics, used to infer regionally enriched gene expression, suggested dynamic alterations in fibroblast and vascular smooth muscle cell (VSMC) states during neointima formation. Specifically, we identified the emergence of HES1+ and matrix metalloproteinase 2- and 14-positive (MMP2+/MMP14+) expression in VSMCs and fibroblasts, respectively, during neointima formation. Furthermore, our data suggest that MIR647, identified through screening, maintains VSMC contractile gene expression. Our findings suggest dynamic transcriptomic and proteomic changes during neointima formation in human veins and provide useful mechanistic information for the pathogenesis of SV graft disease.NEW & NOTEWORTHY Using multiomics and spatial transcriptomics, we uncover dynamic molecular and cellular changes driving neointima proliferation in human saphenous veins, the most common conduit for bypass surgery. Our study highlights sex- and body mass index-associated differences, novel fibroblast and smooth muscle cell states, and a role for microRNA-647 in preserving vascular contractile phenotype. These findings provide new insight into the mechanisms of vein graft failure and may guide future strategies to improve coronary bypass outcomes.

Humans↗

PubMed2026

Plasticity in a bacterial global regulatory switch that drives a shift in antibiotic resistance and virulence.

Antibiotic resistance and expression of virulence factors impact the outcome of infection by Pseudomonas aeruginosa. Pathogenesis is often modelled using the PAO1 reference strain but laboratory lineages vary in the sequence and activity of MexT, a global regulator impacting virulence, biofilm formation, and ciprofloxacin resistance. We defined the impact of active versus inactive MexT in PAO1 and observed transcriptomic changes affecting the expression of ~900 genes. Phenotyping revealed altered metabolism, antibiotic resistance, and virulence, resulting in striking variation across a 'single' model organism. We propose that antibiotic resistance promotes plasticity in mexT accounting for variation across lineages. We introduced antibiotic resistance into clinical P. aeruginosa isolates and observed mutations in mexT when selective pressure was removed, supporting the proposed evolutionary pathway. Overall, we have demonstrated the transcriptomic basis of MexT as a phenotypic switch in PAO1 and implicated antibiotic resistance as a cause of changes in mexT. Furthermore, MexS/MexT-regulated efflux is implicated in the antibiotic stress response and virulence, helping identify the mechanisms for rapid phenotypic switching through mexT and confirming that PAO1 is unlike most isolates. Improved understanding of the regulatory changes linked to antibiotic resistance is particularly relevant to P. aeruginosa where cycles of antibiotic treatment are common.

antibiotic resistance↗

PubMed2026

Luteolin is associated with alleviation of cigarette smoke-induced cellular senescence and inflammation in mice involving the CREB/c-Fos/NQO1 pathway.

Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD) and is closely associated with cellular senescence. Previous studies have demonstrated the efficacy of luteolin in treating aging-related symptoms. This study aims to elucidate the therapeutic potential of luteolin against CS-induced cellular senescence. Using a CS-exposed mouse model and cigarette smoke extract (CSE) treated mouse lung epithelial cells (TC-1), we demonstrate that luteolin significantly attenuates CS-induced histopathological alterations and inflammatory cytokine release while alleviating cellular senescence. Transcriptome sequencing suggests that NQO1 and Fos may serve as a common molecular target for both CS-induced pathology and luteolin treatment. Subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) enrichment analysis and pathway validation experiments revealed that the cAMP agonist Forskolin inhibits senescence marker expression by activating the CREB pathway, exhibiting a mechanism similar to that of luteolin. Notably, luteolin activation of this pathway may not depend on PKA activation. Ultimately, the study found that luteolin mitigates inflammatory responses and prevents lung epithelial cell senescence via the CREB/c-Fos/NQO1 pathway. These findings not only suggest the pivotal role of NQO1 in regulating CS-induced cellular senescence but also underscore the potential of luteolin as a therapeutic drug.

Animals↗

PubMed2026

Reduced expression of Brain Expressed X-linked genes in Alzheimer's disease.

BackgroundAltered expression of Brain Expressed X-linked (BEX) genes has been implicated in Alzheimer's disease (AD) with inconsistencies and a lack of experimental confirmation.ObjectiveThis study aims to characterize BEX expression patterns, examine the association of their expression with AD pathology, and investigate cellular changes induced by altered BEX expression.MethodsWe integrated bulk and single-cell transcriptomics datasets to characterize cortical BEX expression changes in 5xFAD mice and AD patients, which were validated by RT-qPCR in postmortem AD cortical tissue. We manipulated the expression of BEX genes in SH-SY5Y cells and examined changes in oxidative stress.ResultsCortical expression of BEX genes was reduced in AD. With the dysregulation being more pronounced at a later stage of the disease, the reduction was closely related to the impairment of synaptic transmission and oxidative phosphorylation in excitatory neurons. Consistent with these, BEX3 knockdown increased oxidative stress.ConclusionsOur findings suggest that reduced BEX expression in neurons appears to be a contributing factor to AD pathogenesis and BEX depletion may increase oxidative stress.

Alzheimer Disease↗

PubMed2026

Spatial transcriptomics of primary and metastatic ALK-rearranged NSCLC reveals site-specific adaptations.

INTRODUCTION: Genetic alterations and the tumor microenvironment (TME) influence treatment response in anaplastic lymphoma kinase-rearranged non-small cell lung cancer (ALK+ NSCLC). This study maps site-specific TME adaptations and exploratory risk-associated signatures in lymph node metastases (LNT) to investigate metastatic evolution. METHOD: We applied spatial transcriptomics to profile tumor (PanCK+) and stromal (PanCK-) compartments in a pilot cohort of 16 cases: primary lung tumors (LT, n = 3), LNT (n = 10), and brain metastases (BT, n = 3), with three site-matched non-tumor controls. LNT-derived prognostic signatures were evaluated using The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA LUAD) cohorts. RESULTS: Distinct, site-specific TME features were observed. LNT stroma was enriched in fibroblasts and macrophages, while tumor segments showed increased neutrophils. BT exhibited a macrophage-associated immunosuppressive TME. Tumor cells evolved divergently: LT retained pulmonary identity and showed trend towards translation-associated programs, LNT cells shifted toward senescence and epigenetic remodeling, and BT cells showed activation of Class A/1 (Rhodopsin-like) receptor, GPCR and drug metabolism pathways. In LNT, exploratory risk-associated differences were observed. Low-risk cases (n = 6) showed adaptive immune signatures, whereas high-risk cases (n = 4) showed enrichment for stromal MET signaling and stress-response pathways. Because treatment exposure differed markedly between the risk groups, these observations should be interpreted as hypothesis-generating. TCGA LUAD analysis suggested the broader biological relevance of immune-associated markers, but reflected general LUAD rather than ALK+ specific biology. Discordant associations for GCLC and TIMP1 underscored the importance of spatial context. CONCLUSION: Site-specific microenvironments may influence tumor adaptation across metastatic niches in ALK+ NSCLC. The exploratory risk-associated findings require validation in larger, uniformly treated cohorts.

Humans↗

PubMed2025

Immune landscape and novel therapeutic targets of epidermal growth factor receptor and anaplastic lymphoma kinase wild type never-smoker lung adenocarcinoma.

BACKGROUND: Never-smoker lung adenocarcinoma (NSLA) exhibits distinct immunosuppressive profiles and a lower tumor mutation burden compared with lung adenocarcinoma in smokers. These correlate with poor responses to immune checkpoint inhibitors. In this study, we aimed to elucidate the tumor-immune microenvironment of NSLA without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations and identify novel therapeutic targets. METHODS: We analyzed genome, transcriptome, and proteomic data from 102 NSLA tumor samples and 16 normal adjacent tissues. We classified tumors into distinct immune clusters (IC) based on gene signatures by profiling the tumor-infiltrating immune cells. RESULTS: The tumors were stratified into three ICs: hot, intermediate, and cold. Notably, only 21 (20.6%) patients exhibited hot IC enriched in cytotoxic T cells, natural killer cells, and B-cell signatures, which correlated with improved recurrence-free survival. Cold ICs (37.3%) exhibited higher myeloid-derived suppressor cell (MDSC) levels and M2 macrophage signatures, with poor immune cell infiltration and relatively low stimulatory cytokines and chemokines expression. CEACAM1, and NECTIN2 were upregulated in intermediate and cold ICs and correlated with MDSC and M2 macrophage infiltration. High expression of these genes was associated with poor survival outcomes. Protein-protein network analysis of 20 upregulated molecules associated with cancer- and driver-related proteins in cold IC identified XPO 1 as a key component. CONCLUSION: Our proteogenomic analysis highlighted the immunosuppressive properties of NSLA without EGFR and ALK alterations and identified novel therapeutic targets. These findings may provide novel treatment strategies that could improve the clinical outcomes of patients with NSLA.

Humans↗

PubMed2026

Epithelial tumor suppressor deletion promotes neuroendocrine differentiation in bladder cancer and reveals homoharringtonine as a candidate vulnerability.

Neuroendocrine bladder carcinoma (NEBC) is a highly aggressive malignancy with unresolved lineage determinants and limited preclinical models, hindering mechanistic investigation and therapeutic development. Here, we sought to assess whether bladder epithelial-derived models are competent to acquire neuroendocrine lineage programs under defined tumor suppressor alterations and to identify candidate therapeutic vulnerabilities in these systems. We integrated genomic and transcriptomic analyses of human NEBC with genetically engineered mouse models, epithelial-derived bladder organoids, and patient-derived NEBC models. Human NEBC exhibited dominant RB1 and TP53 alterations and an epithelial transcriptional continuum consistent with lineage plasticity. In vivo, intravesical Adeno-Cre-mediated tumor suppressor deletion predominantly generated sarcoma-like tumors, whereas epithelial-restricted organoid models recapitulated the molecular and neuroendocrine features of human NEBC, supporting epithelial lineage competence for neuroendocrine differentiation. Patient-derived models and human NEBC specimens further supported epithelial identity in NEBC. Using these complementary platforms, drug screening identified homoharringtonine (HHT) as a candidate therapeutic vulnerability in the tested NEBC systems. HHT suppressed neuroendocrine marker expression, induced apoptosis, and attenuated IL6-JAK-STAT3 signaling. Together, these findings describe complementary epithelial-derived NEBC models and support further investigation of HHT as a candidate therapeutic vulnerability.

Journal Article↗