The Journal of Pathology最新文献

Germline variations contribute to esophageal squamous cell carcinoma (ESCC) susceptibility. We identified a germline deletion (exons 7-8) in HIF3A in an ESCC family and investigated its functional impact using CRISPR/Cas9-engineered cells and Hif3a-eKO1 mice (heterozygous for exons 7-8 deletion). Multi-omics analysis of Hif3a-eKO1 and WT mice revealed dysregulated pathways in normal esophagus and during 4NQO-induced carcinogenesis, with key biomarkers validated by immunohistochemistry. Hif3a deficiency enhanced ESCC cell proliferation and invasion in vitro and accelerated 4NQO-induced tumorigenesis in vivo, with Hif3a-eKO1 mice developing more and larger neoplastic lesions. Multi-omics analysis revealed downregulation of cytokeratin-related genes (notably Krt17) and γδ T cells in normal esophagus of Hif3a-eKO1 compared with WT. Consistently reduced Krt17 expression in Hif3a-eKO1 was confirmed by both esophageal immunohistochemistry and cellular Western blot analyses. During 4NQO-induced carcinogenesis, Hif3a deficiency upregulated DNA damage response markers, including Krüppel-like factor 4 (Klf4) and ATR serine/threonine kinase (Atr). Notably, epithelial cells with abundant γH₂AX foci lacked Krt17 expression, while Krt17-positive cells showed minimal γH₂AX foci. Heterozygous germline Hif3a deletion (exons 7-8) may promote ESCC by disrupting esophageal barrier function-impairing Krt17-mediated epithelial integrity and reducing γδ T cells-while exacerbating genomic instability. These findings reveal ESCC predisposition mechanisms and therapeutic targets. © 2026 The Pathological Society of Great Britain and Ireland.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor originating from calcitonin producing C-cells and accounts for 1-5% of thyroid cancers. Total thyroidectomy is curative in localized disease (N0), whereas lymph node metastases (N1) are associated with poorer prognosis. However, the molecular mechanisms driving the metastatic shift remain poorly understood. This study aimed to identify miRNA features linked to metastatic spread in MTC, focusing on the transition from N0 to N1. Co-expression networks were constructed for N0 and N1 tumors, and differential connectivity analysis was used to identify key miRNAs acting as regulatory hubs. Functional annotation of their target genes was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Reactome pathway analyses. Validation experiments were carried out in MTC cells to evaluate the effects of selected miRNAs on cell proliferation, survival, and MAPK pathway activation. Network analysis revealed distinct miRNA co-expression patterns between N0 and N1 tumors. Differential network analysis highlighted miR-145-3p as a central regulatory hub, exhibiting 29 altered co-expression changes and a marked loss of connectivity in N1. Target enrichment identified 59 validated genes, including key oncogenic drivers such as MYC, PTEN, BCL2, PIK3CA, AKT1, and MAPK7. In MTC cells, simultaneous inhibition of miR-145-3p together with its top co-expressed miRNAs increased proliferation and survival, and enhanced ERK phosphorylation, indicating MAPK pathway activation and a shift toward a more aggressive phenotype. In conclusion, this study identifies a miRNA regulatory hub centered on miR-145-3p that is associated with metastatic progression and highlights the value of network-based approaches in uncovering mechanisms of cancer dissemination. © 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.

Invasive mucinous adenocarcinoma (IMA) of the lung is a distinct subtype of lung adenocarcinoma with unique clinicopathologic features; however, its histogenesis remains incompletely understood. Although mucinous metaplasia has been suspected as a precursor lesion, direct molecular evidence supporting this progression is limited. In this study, we applied morphology-guided spatial transcriptomics to investigate epithelial lineage relationships across the mucinous spectrum of lung lesions. Formalin-fixed, paraffin-embedded lung tissues from 26 patients were analyzed using the GeoMx digital spatial profiling platform. A total of 118 cytokeratin-positive regions of interest representing normal bronchioles, bronchiolar metaplasia, mucinous metaplasia, mucinous dysplasia, IMA, nonmucinous terminal respiratory unit-type adenocarcinoma, squamous metaplasia/dysplasia, and squamous cell carcinoma were profiled. Spatial transcriptomic data were integrated with two independent public cohorts and mapped to the Human Lung Cell Atlas for epithelial cell-type assignment. Unsupervised clustering identified a distinct mucinous cluster comprising IMA and most mucinous dysplasia regions, characterized by enrichment of gastric-type differentiation markers, including MUC5AC, MUC6, TFF1, TFF2, and CLDN18. Label-transfer analysis demonstrated that mucinous metaplasia and dysplasia were predominantly associated with club and goblet cell identities, whereas IMAs showed enrichment of club and goblet signatures. In contrast, nonmucinous adenocarcinomas consistently aligned with alveolar type 2 cell identity across all datasets. Immunohistochemistry confirmed uniform CLDN18 expression in IMAs and its absence in nonmucinous adenocarcinomas. These findings provide spatial transcriptomic evidence supporting a club cell-associated mucinous pathway in lung tumorigenesis and identify CLDN18 as a defining molecular feature of IMA. © 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.

The progression of colorectal cancer (CRC) is critically regulated by cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), yet the specific molecular mechanisms by which CAFs influence CRC remain unclear. This study reveals the mechanism by which CAFs promote CRC malignant progression and immune suppression through metabolic reprogramming. Findings indicate that lactate secreted by CAFs induces lactylation modifications of histone H3K9La and H3K18La, thereby upregulating the expression of key cholesterol synthesis enzymes DHCR7 and CYP51A1, which in turn enhances the malignant properties of CRC cells. In vivo and in vitro experiments confirm that inhibiting DHCR7 significantly reverses CAF-mediated tumor promotion. More importantly, this study revealed that CAF-induced CRC cells with elevated cholesterol metabolism deliver DHCR7 to CD8⁺ T cells via exosomes, thereby triggering mitochondrial dysfunction and driving the cellular senescence process. This senescence manifests as reduced IFN-γ secretion capacity and enhanced senescence-associated secretory phenotype (SASP). In summary, this study systematically elucidates the central role of the CAF-CRC cell-CD8⁺ T cell regulatory axis: CAF-derived lactate modulates cholesterol metabolism in CRC cells via histone lactylation. Subsequently, CRC cells with enhanced cholesterol metabolism deliver DHCR7 to CD8⁺ T cells via exosomes, inducing mitochondrial dysfunction, which in turn leads to CD8⁺ T-cell senescence and immunosuppression. This provides a new theoretical foundation and therapeutic rationale for metabolic-immune combination strategies in CRC. © 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.

Ductular reactions (DRs) are dynamic and complex multicellular responses that occur as a result of various hepatic injuries. Precise identification and quantification of the extent of DRs is a cornerstone of pre-clinical modelling of liver disease, with links to inflammation, fibrosis, regeneration, and disease severity. Here, we apply a deep learning model, Deep Understanding Convolutional Kernel (DUCK-Net), to the automated detection and segmentation of DRs in whole-slide histopathological images of murine models of liver damage. Following annotation of a training dataset by a specialist liver histopathologist, we demonstrate accelerated performance and accurate detection, achieving a mean Dice coefficient (model-expert segmentation overlap) of 85.4% and a specificity of 98%, indicating minimal false positives. Evaluation of model validity and utility was achieved with a histological time course of cholestatic injury and recovery using 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet (DDC) in mice. When assessed against a multiple linear regression model incorporating core epithelial and stromal components of the DR as quantified using immunohistochemistry (IHC), DUCK-Net predicted the spatiotemporal response to injury and repair/resolution with a coefficient of determination (R²) of 0.88. Moreover, DUCK-Net kinetics strongly correlated with published spatial transcriptomic (Stereo-seq) analysis of the DDC model, demonstrating that H&E-based segmentation captured molecular DR dynamics comparable to or exceeding that of individual IHC markers without the need for immunostaining. DUCK-Net provides a novel and accessible platform for rapid, accurate histological quantification of liver injury reflective of the matrix-rich, multicellular regenerative niche observed in DRs. © 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.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in STK11, and is characterized by gastrointestinal hamartomatous polyps, the recurrent development of which significantly impacts patients' quality of life. While stromal cells have been implicated in PJS polyp formation, their specific characteristics remain unclear. Domènech-Moreno et al identify polyp-enriched crypt top fibroblasts (pCTFs) as the pathogenic fibroblast population and demonstrate that interleukin (IL)-11, a major secretory factor produced by these cells, serves as a critical mediator linking STK11 deficiency to epithelial proliferation. The study reveals that Stk11 loss triggers IL-11 expression, which in turn reinforces the pathogenic pCTF phenotype through autocrine signaling, forming a feedforward loop. Importantly, IL-11 neutralization significantly reduces polyp formation in a faithful mouse model, providing strong preclinical evidence for therapeutic translation. This work represents a significant advance in our understanding of PJS pathogenesis and establishes IL-11 as a promising therapeutic target. Future investigations into the effects of IL-11 neutralization on established polyps will further refine the translational potential of these findings for preventive intervention strategies. © 2026 The Pathological Society of Great Britain and Ireland.

Serum response factor (SRF) is a ubiquitously expressed transcription factor that regulates immediate early genes, cytoskeletal organization, and muscle differentiation. Although SRF plays critical roles in development and cell growth, genomic alterations of SRF have long appeared absent in human neoplasms. Recently, however, recurrent SRF gene rearrangements have been identified in a spectrum of soft tissue tumors with myogenic features, including rhabdomyosarcomas, perivascular tumors, inflammatory myofibroblastic tumors, myoepitheliomas and peripheral nerve sheath tumors. This review summarizes current knowledge on SRF fusion genes and their biological and clinical implications. SRF fusions retain the N-terminal DNA-binding domain while replacing the native transactivation domain with that of a partner protein, frequently a transcription factor or co-activator. This structural configuration leads to constitutive activation of SRF and dysregulation of transcriptional programs related to myogenesis, cytoskeleton organization, and, in some cases, inflammatory signaling. SRF-rearranged tumors predominantly affect children, usually display low-grade behavior, and are often cured by complete surgical resection, although rare recurrences and metastases have been reported. Within perivascular myoid neoplasms, SRF-rearranged tumors show consistent phenotypic and clinical features, supporting their recognition as a distinct tumor entity, whereas SRF fusions identified in rhabdomyosarcomas and rare isolated cases likely represent separate biological contexts. Understanding SRF fusion-driven transcriptional dysregulation provides insights into tumorigenesis and may inform future diagnostic and therapeutic strategies in myoid soft tissue neoplasms. © 2026 The Pathological Society of Great Britain and Ireland.

Pancreatic polypeptide (PP) and neuropeptide Y4 receptor (Y4R) are part of a conserved system that is involved in appetite regulation, gastrointestinal functions, and energy homeostasis. Experimental evidence suggests that PP-Y4R signaling might play a role in various extrahepatic cancer types, but the exact mechanisms remain unclear. Moreover, the potential role of PP-Y4R crosstalk in hepatocellular carcinoma (HCC) was unknown and has been addressed in this study. We found that the ligand (PP) and the receptor (Y4R) were markedly overexpressed in HCC cells and in patient-derived tissues, which was correlated with a poor prognosis. Mechanistically, we found that PP promoted migration of HCC cells mediated via activation of extracellular signal-regulated kinase (ERK) signaling. Knockdown of Y4R or pharmacological inhibition of Y4R decreased migration, clonogenicity, and proliferation of HCC cells and induced a G1-cell cycle arrest and cellular senescence. Conversely, activation of the PP-Y4R axis was sufficient to overcome both spontaneous and sorafenib-induced senescence, which was mediated by ERK signaling. Our study provides novel insights into the pro-tumorigenic roles of PP and Y4R in HCC, indicating that PP-Y4R crosstalk might represent a potential novel therapeutic target. © 2026 The Pathological Society of Great Britain and Ireland.

The axillary lymph node remains a cornerstone of breast cancer staging and therapeutic decision-making, yet it is still largely interpreted through a static anatomical framework. Emerging evidence challenges this paradigm, positioning tumor-draining lymph nodes as dynamic immunological ecosystems that actively regulate tumor progression and host response. In this context, Llewellyn et al introduce a quantitative framework to characterize fibroblastic reticular cell network topology and link nodal architecture to clinical outcomes. By quantifying features such as lacunarity, branching, and alignment in a breast cancer cohort, the authors show that fibroblastic reticular cell network organization is associated with prognosis in a context-dependent manner. While this approach represents a significant conceptual and methodological advance, its biological interpretation remains limited by the absence of functional validation and integrated immune profiling. Accumulating evidence indicates that lymph node microenvironments undergo profound immune reprogramming, highlighting the close interdependence between stromal topology and immune composition. These findings suggest that structural features alone may reflect distinct underlying biological states. Integrating spatial metrics with immune characterization may refine current staging systems, improve risk stratification, and ultimately inform future evolution of staging classifications by incorporating functional and spatial dimensions of nodal involvement. © 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.

Recently, we suggested the combination of chemotherapy and P2RX4 inhibition as a promising novel therapeutic approach for P2RX4-expressing epithelial tumors to prevent paracrine resistance. Here, we aimed to assess whether determining P2RX4 expression status in colorectal and pancreatic cancer patients would allow stratification of potentially responsive patients. Therefore, P2RX4 expression levels were determined by RNA sequencing and immunohistochemistry. Subcellular localization of P2RX4 isoforms was analyzed in HeLa cells and patient-derived tumor organoids. In contrast to its RNA expression profile, P2RX4 protein levels exhibited differential regulation in human colorectal and pancreatic cancer epithelia due to alternative splicing. Interpatient heterogeneity was greater in colorectal cancer than in pancreatic cancer. Notably, these variations in expression did not correlate with overall patient survival. Alternative P2RX4 transcripts gave rise to functionally distinct protein isoforms that differed in subcellular localization and total protein abundance. Only the correctly spliced, canonical P2RX4 isoform was localized to the plasma membrane and was capable of mediating downstream signaling. Accordingly, P2RX4 inhibition in combination with chemotherapy was effective exclusively in patient-derived tumor organoids expressing the canonical P2RX4 transcript. In summary, immunohistochemical, but not transcriptomic, assessment of P2RX4 expression enabled the prediction of sensitivity to combinatorial treatment and facilitated the identification of patients who may benefit from P2RX4 inhibition during chemotherapy. Given the lower degree of heterogeneity observed in pancreatic cancer, this tumor entity may represent a promising candidate for early-phase clinical evaluation of chemotherapy combined with P2RX4 inhibition. © 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.