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Cross-tissue atlas of mucosa-associated lymphoid tissue lymphomas reveals intratumoral heterogeneity and microenvironmental subtypes.
Mucosa-associated lymphoid tissue (MALT) lymphoma, a common primary extranodal B cell lymphoma that arises in diverse mucosal tissues, has a pathogenesis closely linked to the supportive lymphoma microenvironment (LME). However, its microenvironmental heterogeneity and therapeutic implications remain unclear. Here, we report a cohort of 89 MALT lymphoma samples from multiple anatomical sites, profiled by bulk (n = 89), single-nucleus (n = 16), and spatial (n = 9) RNA sequencing. Integrative analysis of 120 bulk transcriptomes from our cohort and two independent cohorts, guided by cell-type-resolved signatures derived from single-nucleus data, identifies three LME subtypes: mesenchymal, inflammatory, and depleted. Single-cell and spatial mapping further reveal distinct cellular compositions and interaction networks across these subtypes, particularly in relation to B cell activation and angiogenesis, suggesting distinct biological states and subtype-specific therapeutic vulnerabilities. This study establishes an LME-based classification framework for MALT lymphoma with biological and clinical relevance.
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Integrated Transcriptome Profiling and Pan-Cancer Analyses Reveal Oncogenic Networks and Tumor-Immune Modulatory Roles for FABP7 in Brain Cancers.
Fatty acid binding protein 7 (FABP7) is a multifunctional chaperone involved in lipid metabolism and signaling. It is primarily expressed in astrocytes and neural stem cells (NSCs), as well as their derived malignant glioma cells within the central nervous system. Despite growing evidence for FABP7's tumor-intrinsic onco-metabolic functions, its mechanistic role in regulating the brain tumor immune microenvironment (TIME) and its impact on prognosis at the molecular level remain incompletely understood. Utilizing combined transcriptome profiling and pan-cancer analysis approaches, we report that FABP7 mediates the expression of multiple onco-immune drivers, collectively impacting tumor immunity and clinical outcomes across brain cancer subtypes. An analysis of a single-cell expression atlas revealed that FABP7 is predominantly expressed in the glial lineage and malignant cell populations in gliomas, with nuclear localization in their parental NSCs. Pathway and gene enrichment analysis of RNA sequencing data from wild-type (WT) and Fabp7-knockout (KO) mouse brains, alongside control (CTL) and FABP7-overexpressing (FABP7 OV) human astrocytes, revealed a more pronounced effect of FABP7 levels on multiple cancer-associated pathways. Notably, genes linked to brain cancer progression and tumor immunity (ENO1, MUC1, COL5A1, and IL11) were significantly downregulated (>2-fold) in KO brain tissue but were upregulated in FABP7 OV astrocytes. Furthermore, an analysis of data from The Cancer Genome Atlas (TCGA) showed robust correlations between the expression of these factors, as well as FABP7, and established glioma oncogenes (EGFR, BRAF, NF1, PDGFRA, IDH1), with stronger associations seen in low-grade glioma (LGG) than in glioblastoma (GBM). TIME profiling also revealed that the expression of FABP7 and the genes that it modulates was significantly associated with prognosis and survival, particularly in LGG patients, by influencing the infiltration of immunosuppressive cell populations within tumors. Overall, our findings suggest that FABP7 acts as an intracellular regulator of pro-tumor immunomodulatory genes, exerting a synergistic effect on the TIME and clinical outcomes in brain cancer subtypes.
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Construction of a solid Cox model for AML patients based on multiomics bioinformatic analysis.
Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The bone marrow (BM) microenvironment in AML plays an important role in leukemogenesis, drug resistance and leukemia relapse. In this study, we aimed to identify reliable immune-related biomarkers for AML prognosis by multiomics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and constructed a LASSO-Cox regression model to predict the prognosis of AML using multiomics bioinformatic analysis data. This was followed by independent validation of the model in the GSE106291 (n=251) data set and mutated genes in clinical samples for predicting overall survival (OS). Molecular docking was performed to predict the most optimal ligands to the genes in prognostic model. The single-cell RNA sequence dataset GSE116256 was used to clarify the expression of the hub genes in different immune cell types. According to their significant differences in immune gene signatures and survival trends, we concluded that the immune infiltration-lacking subtype (IL type) is associated with better prognosis than the immune infiltration-rich subtype (IR type). Using the LASSO model, we built a classifier based on 5 hub genes to predict the prognosis of AML (risk score = -0.086×ADAMTS3 + 0.180×CD52 + 0.472×CLCN5 - 0.356×HAL + 0.368×ICAM3). In summary, we constructed a prognostic model of AML using integrated multiomics bioinformatic analysis that could serve as a therapeutic classifier.
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Computational discovery of novel colony-stimulating factor-1 receptor as a potential therapeutic biomarker in osteosarcoma and a novel inhibitor from herbal sources.
Osteoclast differentiation and activation pathways drive abnormally enhanced bone resorption in osteosarcoma, and have thus emerged as potential therapeutic targets for this malignancy. However, the diagnostic value of osteoclast differentiation-related genes (ODRGs) in osteosarcoma remains largely uncharacterized. The present study first analyzed the expression profiles of ODRGs in osteosarcoma using multiple Gene Expression Omnibus datasets. Analysis of single cell RNA-sequencing data from osteosarcoma tissues demonstrated that colony-stimulating factor-1 receptor (CSF1R), a key ODRG, was widely expressed in osteoblasts and monocyte/macrophage lineages within the osteosarcoma microenvironment. Subgroup analysis further revealed that patients with osteosarcoma in the low-CSF1R expression group exhibited significantly increased sensitivity to immune checkpoint inhibitors compared with those in the high-CSF1R expression group. Furthermore, pan-cancer analysis across The Cancer Genome Atlas datasets demonstrated that CSF1R expression was aberrantly regulated in multiple tumor types and strongly correlated with the expression levels of immune checkpoint markers and the infiltration levels of immune cells. Functional validation experiments confirmed that treatment with CSF1R-specific inhibitors significantly reduced the viability of the MG63 and Saos-2 cell lines. To identify novel, natural-product-derived CSF1R inhibitors, structure-based virtual screening was combined with in vitro experimental assays (CCK-8 and western blotting). Among the validated candidates, sarsasapogenin, a compound identified from the screen, effectively suppressed CSF1R protein expression and inhibited the proliferation of both MG63 and Saos-2 cells in a dose-dependent manner. Collectively, the present findings highlight CSF1R as a clinically promising diagnostic biomarker and therapeutic target for osteosarcoma.
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SNRPB2 in the pan-cancer landscape: A bioinformatics exploration and validation in hepatocellular carcinoma.
Aberrant splicing is a significant contributor to gene expression abnormalities in cancer. SNRPB2, a component of U2 small nuclear ribonucleoprotein particles (snRNPs), contributes to the assembly of the spliceosome, the molecular machinery responsible for splicing. To date, few studies have investigated the role of SNRPB2 in tumorigenesis. We examined data sourced from various public databases, such as The Cancer Genome Atlas(TCGA), the Clinical Proteomic Tumor Analysis Consortium(CPTAC), and Gene Expression Omnibus(GEO). Our investigation included gene expression, genomic and epigenomic scrutiny, gene set enrichment assessment(GSEA), and immune cell infiltration evaluation. Furthermore, we performed empirical validation to ascertain the impact of SNRPB2 suppression on the proliferation and migration of liver cancer cells. Analysis of gene expression revealed widespread upregulation of SNRPB2 across a spectrum of cancer types, with heightened levels of SNRPB2 expression in numerous tumors linked to unfavorable prognosis. Genomic and epigenomic assessments revealed connections between SNRPB2 expression and variations in SNRPB2 copy number, DNA methylation patterns, and RNA modifications. Through gene set enrichment analysis, the involvement of SNRPB2 in vital biological processes and pathways related to cancer was identified. Furthermore, scrutiny of immune cell infiltration suggested a potential relationship between SNRPB2 and the tumor microenvironment, which was reinforced by multiple single-cell sequencing profiles. Subsequent experimental validation revealed that silencing SNRPB2 effectively impeded the proliferation and migration of liver cancer cells. Taken together, these findings underscore the prospective utility of SNRPB2 as a prognostic biomarker and a promising candidate for immunotherapy in cancer. It is necessary to engage in additional exploration into its underlying mechanisms and clinical treatment potential.
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Mitochondrial-impaired ductal epithelium fuels TLS formation in Sjögren's disease.
OBJECTIVES: Progressive inflammatory cell infiltration within salivary glands is a defining feature of advanced Sjögren's disease (SjD) and is frequently accompanied by tertiary lymphoid structure (TLS) formation. However, the initial events driving this pathogenic trait in SjD progression are not fully understood. METHODS: We collected 848 labial salivary gland (LSG) biopsies (668 SjD, 180 non-SjD) and profiled bulk transcriptomics, single cell RNA-sequencing (scRNA-seq), spatial transcriptomics, transmission electron microscopy (TEM), and histology. In vivo functional validation was performed in NOD/ShiLtj mice with spontaneous SjD via nicotinamide mononucleotide administration to restore mitochondrial function. RESULTS: Mitochondrial function was impaired in LSG tissues from SjD patients, with functional validation in NOD/ShiLtj mice showing attenuated ductal injury and reduced immune cell infiltration. scRNA-seq analyses revealed that each LSG cellular subset harbours a distinct mitochondrial transcriptional profile, which we identified here as a molecular fingerprint for individual cellular subsets. TEM established an ultrastructural atlas of human minor salivary glands, showing that striated duct (SD) cells are most enriched with mitochondria among all epithelial subtypes. In SjD LSGs, particularly those with TLSs, profound mitochondrial dysfunction and impaired oxidative phosphorylation were observed. A previously unrecognized proinflammatory SD subset, SD-C1 (marked by matrix metalloproteinase 7), was markedly expanded in SjD-TLS+ tissues and exhibited severe mitochondrial impairment. SD-C1 cells showed enhanced crosstalk with T cells, B cells, and macrophages via immune signalling pathways and were spatially colocalized with immune cell aggregates in periductal regions where TLSs formed. CONCLUSIONS: Mitochondrial injury in SD epithelial cells emerges as a trigger of TLS formation and progressive autoimmunity in SjD. Therapies that preserve mitochondrial integrity and functionality in ductal cells may mitigate salivary gland degeneration during SjD progression.
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Single-cell landscape of undifferentiated pleomorphic sarcoma.
Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive malignant soft tissue tumor with a poor prognosis; however, the identity and heterogeneity of tumor populations remain elusive. Here, eight major cell clusters were identified through the RNA sequencing of 79,569 individual cells of UPS. UPS originates from mesenchymal stem cells (MSCs) and features undifferentiated subclusters. UPS subclusters were predicted to exist in two bulk RNA datasets, and had a prognostic value in The Cancer Genome Atlas (TCGA) dataset. The functional heterogeneity of malignant UPS cells and the immune microenvironment were characterized. Additionally, the fused cells were innovatively detected by expressing both monocyte/macrophage markers and other subcluster-associated genes. Based on the ligand-receptor interaction analysis, cellular interactions with epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) were abundant. Furthermore, 73% of patients with UPS (48/66) showed positive EGFR expression, which was associated with a poor prognosis. EGFR blockade with cetuximab inhibited tumor growth in a patient-derived xenograft model. Our transcriptomic studies delineate the landscape of UPS intratumor heterogeneity and serve as a foundational resource for further discovery and therapeutic exploration.
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Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer.
BACKGROUND: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. METHODS: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2 , CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2/BrafV600E/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2 -/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. RESULTS: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.
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Pan-cancer multi-omics characterization of calcyphosine and its revealed links to the immune microenvironment and regulatory networks in endometrial carcinoma.
OBJECTIVE: The calcium-dependent activator protein for secretion (CAPS) has emerged as a protein of interest in tumor biology; however, its functional significance in endometrial carcinoma (EC) remains largely unexplored. METHODS: We performed an integrative analysis leveraging bulk RNA sequencing data from The Cancer Genome Atlas, GTEx, and publicly available EC datasets, coupled with gene set enrichment analysis (GSEA) and single-cell transcriptomic profiling. The association between CAPS expression and clinicopathological parameters as well as patient prognosis was systematically assessed. In addition, functional enrichment, intercellular communication, and immune infiltration analyses were conducted to elucidate the molecular and microenvironmental roles of CAPS. In vitro assays were employed to validate the biological effects of CAPS knockdown on EC cell proliferation, migration, and invasion. RESULTS: CAPS was significantly upregulated in early-stage, low-grade, and endometrioid endometrial carcinoma, and its elevated expression was associated with improved patient survival. GSEA indicated that high CAPS expression was correlated with enhanced ribosome biogenesis and oxidative phosphorylation, along with suppression of proliferative signaling, reflecting a metabolically differentiated phenotype. Single-cell transcriptomic analysis revealed that CAPS was specifically enriched in terminally differentiated secretory epithelial cells, promoting epithelial maturation and oxidative metabolism. Furthermore, CAPS-positive cells exhibited extensive crosstalk with immune cells, suggesting a potential role in facilitating anti-tumor immune responses. Functional assays confirmed that CAPS knockdown markedly enhanced EC cell proliferation, migration, and invasion. CONCLUSION: CAPS may act as a tumor suppressor in EC by stabilizing microtubule architecture, reprogramming cellular metabolism, and modulating immune interactions within the tumor microenvironment. These findings highlight CAPS as a promising prognostic biomarker and potential therapeutic target in EC.
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Brain and blood single-cell transcriptomics in acute and subacute phases after experimental stroke.
Cerebral ischemia triggers a powerful inflammatory reaction involving both peripheral leukocytes and brain resident cells. Recent evidence indicates that their differentiation into a variety of functional phenotypes contributes to both tissue injury and repair. However, the temporal dynamics and diversity of post-stroke immune cell subsets remain poorly understood. To address these limitations, we performed a longitudinal single-cell transcriptomic study of both brain and mouse blood to obtain a composite picture of brain-infiltrating leukocytes, circulating leukocytes, microglia and endothelium diversity over the ischemic/reperfusion time. Brain cells and blood leukocytes isolated from mice 2 or 14 days after transient middle cerebral artery occlusion or sham surgery were purified by FACS sorting and processed for droplet-based single-cell transcriptomics. The analysis revealed a strong divergence of post-ischemic microglia, macrophages, and neutrophils over time, while such diversity was less evident in dendritic cells, B, T and NK cells. Conversely, brain endothelial cells and brain associated-macrophages showed altered transcriptomic signatures at 2 days post-stroke, but low divergence from sham at day 14. Pseudotime trajectory inference predicted the in-situ longitudinal progression of monocyte-derived macrophages from their blood precursors into day 2 and day 14 phenotypes, while microglia phenotypes at these two time points were not connected. In contrast to monocyte-derived macrophages, neutrophils were predicted to be continuously de-novo recruited from the blood. Brain single-cell transcriptomics from both female and male aged mice did not show major changes in respect to young mice, but aged and young brains differed in their immune cell composition. Furthermore, blood leukocyte analysis also revealed altered transcriptomes after stroke. However, brain-infiltrating leukocytes displayed higher transcriptomic divergence than their circulating counterparts, indicating that phenotypic diversification into cellular subsets occurs within the brain in the early and the recovery phase of ischemic stroke. In addition, this resource report contains a searchable database https://anratherlab.shinyapps.io/strokevis/ to allow user-friendly access to our data. The StrokeVis tool constitutes a comprehensive gene expression atlas that can be interrogated at the gene and cell type level to explore the transcriptional changes of endothelial and immune cell subsets from mouse brain and blood after stroke.