The Journal of Pathology最新文献

Endometrial stromal sarcomas (ESSs) comprise a heterogeneous group of uterine mesenchymal tumors characterized by diverse morphological features and recurrent molecular alterations. Although molecular classification has substantially improved ESS diagnosis, the relationship between specific genetic alterations and morphological phenotypes remains incompletely understood. We performed an integrated molecular and histopathological analysis of ESS to investigate genotype-phenotype correlations and refine tumor classification. A total of 61 patients with histologically suspected ESSs were initially enrolled, and 51 successfully underwent targeted RNA sequencing, followed by comprehensive morphological reassessment, immunohistochemical evaluation, molecular validation, and clinicopathological correlation. Molecularly confirmed ESSs demonstrated distinct genotype-associated morphological patterns. PHF1-rearranged low-grade ESSs showed a strong association with hypocellular growth and prominent collagenized stroma. Quantitative cellularity analysis further demonstrated significantly lower tumor cellularity in PHF1-rearranged low-grade ESSs compared with JAZF1::SUZ12-rearranged tumors (p < 0.001). High-grade ESSs with YWHAE::NUTM2 and BCOR::ZC3H7B alterations showed higher mitotic activity than low-grade ESSs and demonstrated tongue-like infiltration patterns in both primary and metastatic lesions, indicating that this growth pattern, traditionally emphasized in low-grade ESSs, may represent a broader morphological feature of ESSs. Molecular reassessment led to the reclassification of 10 cases (19.6%, 10/51), identifying tumors with alternative molecular alterations that were initially diagnosed as ESSs based on morphology alone. Among these cases, a uterine sarcoma harboring a novel GATA6::SRF fusion exhibited a low-grade ESS-like morphological phenotype but lacked the characteristic molecular alterations of conventional ESSs, suggesting a potential molecularly defined uterine sarcoma subtype requiring further investigation. Our findings demonstrate that integrated molecular and histopathological analysis extends beyond diagnostic refinement by revealing genotype-phenotype relationships, expanding the molecular spectrum of ESSs and ESS-like uterine sarcomas, and providing new insights into the biological heterogeneity of these rare tumors. © 2026 The Pathological Society of Great Britain and Ireland.

Forkhead box protein C2 (FOXC2) is frequently overexpressed in osteosarcoma (OS) and has been implicated in tumor proliferation and metastasis; however, its role in regulating the tumor immune microenvironment remains poorly understood. In this study, integrative bioinformatics analyses of the TCGA-SARC (The Cancer Genome Atlas sarcoma cohort) dataset were performed to evaluate the clinical significance of FOXC2 in OS. High FOXC2 expression was significantly associated with poorer overall survival in patients with OS (p < 0.001). Functional experiments demonstrated that FOXC2 knockdown significantly reduced the overall viable cell/metabolic signal, migration, and invasion in U-2 OS and SaOS-2 cells (p < 0.05). Mechanistically, FOXC2 was found to regulate the CXCL12/CXCR4 signaling axis. ELISA, RT-qPCR, and western blotting analyses showed that FOXC2 knockdown decreased CXCL12 expression, whereas FOXC2 overexpression significantly increased CXCL12 levels. ChIP-qPCR analysis demonstrated significant enrichment of FOXC2 at the CXCL12 promoter and detectable enrichment at the CXCR4 promoter in SaOS-2 cells, and dual-luciferase reporter assays further showed that FOXC2 overexpression significantly increased CXCL12 promoter activity whereas FOXC2 knockdown reduced it, supporting direct transcriptional regulation of the CXCL12/CXCR4 axis by FOXC2. In macrophage co-culture experiments, FOXC2 knockdown promoted M1-like macrophage polarization and reduced M2-like macrophage markers, whereas activation of CXCR4 partially reversed these effects. Flow cytometric analysis further confirmed that FOXC2 knockdown significantly increased the M1/M2 macrophage ratio. In vivo, FOXC2 knockdown markedly reduced tumor growth and lung metastases in a xenograft mouse model, with tumor volume and lung metastatic burden reduced by approximately 50% and 43%, respectively. Tumor tissues from FOXC2-knockdown mice exhibited increased M1-like macrophage infiltration and reduced M2-like macrophage markers. Together, these findings demonstrate that FOXC2 regulates macrophage polarization and OS progression through transcriptional modulation of the CXCL12/CXCR4 signaling axis, highlighting FOXC2 as a potential regulator of the tumor immune microenvironment in OS. © 2026 The Pathological Society of Great Britain and Ireland.

Pancreatic ductal adenocarcinoma (PDAC) with anaplastic features is a rare and highly aggressive subtype with an extremely poor prognosis. However, the molecular mechanisms underlying anaplastic transformation remain poorly understood. To characterize the anaplastic transformation molecular landscape, we analyzed genomic alterations in 5,997 conventional PDAC and 41 anaplastic carcinoma cases from the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) cohort. Additionally, four PDAC samples from the Kyorin cohort with both tubular and anaplastic components were subjected to spatial transcriptomics using the Visium platform. Differential gene expression and pathway enrichment analyses were performed to identify key molecular drivers. Genomic analysis revealed higher KRAS (90 versus 75%), TP53 (85 versus 60%), and CDKN2A (50 versus 30%) mutation frequencies, but notably fewer SMAD4 mutations (5 versus 20%; p = 0.022), in anaplastic carcinoma than in conventional PDAC. Spatial transcriptomics identified distinct molecular signatures, with epithelial-mesenchymal transition (EMT) pathways significantly enriched in anaplastic regions. Levels of ELF3, an epithelial transcription factor, were consistently downregulated in all anaplastic components. Importantly, we detected a strong inverse correlation between SMAD4 and ELF3 expression in both the bulk RNA sequencing cohort and spatial transcriptomic data. Functional validation using the KC-shSmad4 mouse model demonstrated that increased Smad4 suppressed Elf3 expression and promoted mesenchymal reprogramming. Our findings suggest a novel SMAD4-ELF3 regulatory axis that may contribute to anaplastic transformation in PDAC. The retention of SMAD4 functions coupled with ELF3 downregulation may promote EMT and contribute to tumor dedifferentiation. This SMAD4-ELF3 regulatory axis may provide a framework for identifying therapeutic vulnerabilities in this aggressive PDAC variant and further highlight the utility of spatial transcriptomics for understanding tumor heterogeneity. © 2026 The Pathological Society of Great Britain and Ireland.

Pretreatment prediction of neoadjuvant response remains an unresolved challenge in locally advanced rectal cancer, where management is moving towards risk-adapted and response-oriented treatment strategies. Prediction remains difficult because response reflects interacting tumour-intrinsic, immune, stromal, and spatial processes that are incompletely captured by standard clinical and radiological assessment. From a technology-centred perspective, in this Review we assess how molecular, spatial, image-based, and artificial intelligence-enabled approaches are being used to study and predict response to neoadjuvant treatment from pretreatment biopsies and how readily they may be translated into clinical workflows. Genomic profiling has its clearest current clinical role in identifying hypermutated immune-responsive subgroups, whereas broader genomic, epigenomic, and immune-repertoire markers remain largely investigational. Bulk transcriptomics has generated multiple response signatures with variable reproducibility but has consistently highlighted immune activation, interferon signalling, stromal remodelling, and epithelial-mesenchymal transition as recurrent response-associated programmes; its most feasible clinical route is likely through targeted expression panels rather than open-ended transcriptome profiling. Higher-resolution approaches such as spatial transcriptomic and proteomic platforms refine these observations by localising signals to tumour, immune, and stromal compartments and capturing therapy-induced tissue reorganisation, but they are currently best positioned for deepening biological understanding and nominating rational treatment combinations for future testing. Established platforms such as digital pathology are closer to routine deployment as they build on clinically embedded workflows, although response-prediction algorithms still require robust external validation, calibration, and regulatory-grade implementation. Patient-derived models provide functional systems for testing candidate biomarkers and resistance mechanisms. Multimodal artificial intelligence may support response prediction by identifying complementary signals across data types and distilling complex signatures into parsimonious models suitable for clinical translation. Progress will depend on harmonised, longitudinal, multi-centre studies that couple biological depth with assay standardisation, model reduction, and prospective evidence that response predictors improve patient management. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Calcium oxalate (CaOx) nephropathy is a highly prevalent urological disease worldwide. Gut microbiota dysbiosis and host metabolic dysregulation are recognized as pivotal drivers in disease pathogenesis, yet the underlying mechanisms remain incompletely understood. In this study, by integrating metagenomics and metabolomics, we identified dysregulation of tryptophan metabolites in patients with CaOx nephrolithiasis, with microbiota-derived indole-3-propionic acid (IPA) as the most discriminatory differential metabolite. Oral IPA supplementation markedly reduced renal CaOx crystal deposition and tubular injury in a CaOx nephropathy murine model. Mechanistically, IPA activated the aryl hydrocarbon receptor (AhR), which translocated to the nucleus and transcriptionally upregulated suppressor of cytokine signaling 3 (SOCS3)-a negative regulator of signal transducer and activator of transcription 1 (STAT1)-thereby suppressing STAT1 phosphorylation, alleviating oxalate-induced tubular cell injury and apoptosis, and inhibiting CaOx crystal deposition. Our findings identify tryptophan metabolite alteration as a critical metabolic signature of CaOx nephropathy and demonstrate that microbiota-derived IPA attenuates oxalate-induced renal tubular cell injury and apoptosis via the AhR-SOCS3-STAT1 axis. © 2026 The Pathological Society of Great Britain and Ireland.

Calcium oxalate nephrolithiasis is commonly viewed as a consequence of urinary supersaturation, although crystal retention and renal injury are also influenced by gut microbiota dysbiosis and local tissue environment. In a recent study by Li et al, published in The Journal of Pathology, the authors integrated human metagenomic and metabolomic analyses with mouse and tubular cell models to identify indole-3-propionic acid (IPA) as a key gut-derived metabolite associated with kidney stone disease. Patients with calcium oxalate stones showed altered gut microbial composition and reduced serum IPA levels, which were inversely related to stone burden. In experimental models, IPA supplementation reduced renal crystal deposition, preserved kidney function, and limited tubular injury and apoptosis. Mechanistic studies showed that IPA activated aryl hydrocarbon receptor (AhR) in tubular epithelial cells, increased suppressor of cytokine signaling 3 (SOCS3) expression, and suppressed signal transducer and activator of transcription 1 (STAT1) phosphorylation and nuclear accumulation. These findings were supported by complementary activation, inhibition, knockdown, and overexpression experiments. Collectively, the data suggest that IPA protects renal epithelial cells through the AhR-SOCS3-STAT1 signaling pathway and may offer a potential therapeutic approach for calcium oxalate nephropathy. © 2026 The Pathological Society of Great Britain and Ireland.

Propionic acidemia (PA) is a neurometabolic disorder caused by propionyl-CoA carboxylase deficiency with frequent neurological involvement, yet cell-type-specific mechanisms remain poorly defined. We established human induced pluripotent stem cell (iPSC)-derived astrocytes (iAs) from patients harboring PCCA or PCCB mutations and investigated functional and molecular alterations associated with PA. Both control- and patient-derived iPSCs yielded astrocyte-enriched cultures through a neural progenitor intermediate, with expression of astrocyte-associated markers. Patient iAs showed impaired mitochondrial respiration (lower basal and maximal oxygen consumption and ATP-linked respiration), together with reduced high-affinity uptake of glutamate and glycine neurotransmitters and evidence of disturbed Ca²⁺ homeostasis. They also migrated faster in wound-healing assays and displayed reactive-like features, including increased GFAP and connexin 43 (Cx43) protein levels and elevated AQP4 mRNA levels. Targeted miRNA profiling revealed upregulation of miR-124-3p, miR-9-5p, and miR-125b-5p, concomitant with downregulation of miR-146a-5p, miR-155-5p, and miR-145-5p. Consistent with these changes, reported target genes associated with innate immune signaling (IRAK1, TRAF6, TAB2), astrocyte remodeling (GFAP), and water/ion homeostasis (AQP4) were upregulated. Inflammatory and proliferative markers were likewise increased, including IL1B, TNF, and MKI67. Together, these convergent alterations suggest a phenotype characterized by impaired homeostatic functions and reactive-like features, which may heighten neural network vulnerability under metabolic stress. Collectively, our data support astrocyte dysfunction as a potential contributor to PA neuropathology and highlight patient-derived iAs as a useful model for future mechanistic studies and therapeutic exploration. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Invasion and metastasis in multiple solid tumors are promoted by collective invasion which is organized by leader and follower cells. Yet in colorectal cancer (CRC), biomarkers and mechanisms that specify leader cells remain undefined. Here we identify biomarkers of leader cells and elucidate how they drive CRC collective invasion and metastasis. Using a 3D photoconvertible CRC spheroid model, we isolated leader and follower cells. Transcriptomic, functional and in vivo assays show that GLUT1, PLOD2, and CCL5 in leader cells are indispensable for collective invasion. CCL5 activates PI3K/AKT signaling to up-regulate GLUT1 and PLOD2 in leader cells. Moreover, GLUT1 and CCL5 could serve as specific biomarkers for leader cells in CRC collective invasion, and their co-expression correlates with poor prognosis. Pharmacologic inhibition of GLUT1 and CCL5-CCR5 impairs collective invasion. CCL5 and GLUT1 may define the leader cells and are required for CRC collective invasion as potential key regulators of metabolic shifts and collagen deposition. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Tumour-associated macrophages (TAMs) are known to promote tumour progression in many kinds of malignant tumour, including hepatoblastoma (HB). Based on previous studies, we suggested that TAM-mediated sex-determining region Y-box 9 (SOX9) signal might enhance HB progression. The present study investigated the significance of the SOX9 signal in HB and examined the mechanisms underlying cell–cell interactions between tumour cells and TAMs. Co-culture with human monocyte-derived macrophages increased SOX9 expression in HB cell lines. Immunohistochemical analysis of HB samples revealed a positive correlation between SOX9 expression and TAM infiltration, and SOX9 expression was predominantly observed in the embryonal subtype. Increased SOX9 expression was associated with shorter 5-year recurrence-free and overall survival. Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signalling was found to be involved in macrophage-induced SOX9 upregulation. The Wnt/β-catenin pathway was also activated by co-culture with macrophages and appeared to be upregulated by SOX9 expression. In summary, SOX9 was identified as a poor prognostic factor in HB, with expression enhanced by macrophage-derived factors. The YAP/TAZ and Wnt/β-catenin pathways are critical for cell–cell communication and are linked to SOX9 overexpression. © 2026 The Pathological Society of Great Britain and Ireland.

Neutrophil extracellular traps (NETs) have emerged as critical mediators in the pathogenesis of coronary heart disease (CHD), linking innate immunity, thrombosis, and vascular inflammation. This review offers a comprehensive overview of NETs across the spectrum of CHD, ranging from chronic atherosclerotic plaque development to acute coronary syndrome, myocardial infarction, and ischemia–reperfusion injury. We first summarize the molecular mechanisms underlying NET formation, their regulation, and their dual roles in immune defense and vascular damage. Next, we discuss evidence highlighting the contribution of NETs to plaque initiation, progression, and destabilization, as well as their role in thrombosis following plaque rupture and their impact on myocardial injury and microvascular obstruction during reperfusion. Our review also integrates clinical and translational insights, including circulating NETs as potential biomarkers for disease activity and prognosis, and emerging therapeutic strategies aimed at either inhibiting NET formation or enhancing NET clearance. By positioning NETs within the continuum of coronary pathology, this review highlights their central role in thromboinflammatory cascades and identifies opportunities for innovative interventions to mitigate both acute and chronic cardiac injury. © 2026 The Pathological Society of Great Britain and Ireland.