The Journal of Pathology最新文献

The presence of a single metastatic lesion significantly decreases overall survival in patients with head and neck squamous cell carcinoma (HNSCC), and invasion of malignant keratinocytes is one of the initial steps required for HNSCC metastasis. Histological grading of tumor cell invasion predicts outcome in HNSCC, yet the molecular factors that determine the extent of invasion, and subsequent grading are not fully understood. Using a 3D organ culture model and multiple patient-derived HNSCC keratinocytes representing all major anatomical subsites of the disease, we identified a range of cell states that represent a continuum of epithelial-to-mesenchymal (EMT) characteristics. We also demonstrated how these cell states change in response to TGF-beta stimulation and co-culture with cancer-associated fibroblasts in organ cultures. Using 3D culture models that recapitulate the pattern of invasion seen in primary tumors from which the keratinocytes were derived, we identified distinct clusters of partial-EMT marker expression in individual patient HNSCC keratinocyte populations. Partial-EMT transcription factors were correlated with separate invasive characteristics, and we demonstrated that ZEB2 (a known EMT driver) and HIC1 (a novel EMT driver) are central nodes in HNSCC keratinocyte invasion. Collectively, our findings refine the concepts of partial-EMT and tumor cell invasion, and identify potential therapeutic targets for future development. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Genetic progression models of cancer continue to determine the roadmap of carcinogenesis, although the sequence of genetic events is inferred rather than empirically determined through longitudinal analyses. Here, we present a unique longitudinal study of oral leukoplakia lesions that transformed into carcinoma. Lesions were followed from initial diagnosis through to malignant transformation. For each lesion, biopsies at baseline, the carcinoma, and all available intermediate biopsies were studied for the presence of dysplasia, genomic copy number aberrations, and mutations in selected head and neck cancer genes. Using this information, the phylogenetic history of all carcinomas was reconstructed within the context of applied interventions. In total, 71 biopsies of 21 lesions were studied. The median time to malignant transformation was 60 months. Oral carcinogenesis emerged as a multi-(sub)clonal process. Treatment interventions appeared to impact clonal selection, although lesions always remained after excision. Notably, the lesions demonstrated different routes of progression. A canonical pattern of progression was observed, characterized by longitudinal accumulation of abnormal morphology and genetic changes. However, some lesions followed an alternative, stable pattern of oncogenic progression, with no apparent increase in morphological changes or accumulation of genetic aberrations. This latter pattern appeared to be associated with the development of previously identified ‘copy number quiet’ head and neck tumors. This study provides a novel perspective on the temporal evolution of oral leukoplakia and the different routes to cancer progression and highlights the key role of multiclonal field cancerization in lesion recurrence and cancer development. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Chronic histiocytic intervillositis (CHI) is a rare placental inflammatory lesion increasingly viewed through maternal–foetal immune rejection. In this invited commentary, we discuss how a recent study bolsters the paradigm that CHI represents maternal immune rejection of the semi-allogeneic foetus, analogous to antibody-mediated rejection in organ transplantation. We highlight the shared histological and molecular features between CHI and kidney allograft rejection, including macrophage-dominated inflammation, complement activation, and interferon-gamma-driven gene expression signatures and explore the implications of this common pathogenesis for clinical practice. Recognising CHI as an alloimmune process opens new avenues for early prediction, diagnosis, and intervention. We particularly emphasise the need for early identification of CHI, even in a first pregnancy, where no prior obstetric history exists to raise suspicion. Finally, we outline how transplant immunotherapy principles (e.g. immunosuppression and immune modulation) could transform the management of CHI, and we call for forward-looking research that bridges immune pathology, maternal–foetal medicine, and translational therapeutics to improve pregnancy outcomes. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Sepsis is a potentially lethal syndrome that leads to multiple organ dysfunction. LncRNA GAS5 is closely related to sepsis; however, its detailed functions and mechanism in sepsis-triggered intestinal barrier dysfunction are unclear. In this study, NCM460 cells were stimulated with lipopolysaccharide (LPS) to mimic septic intestinal injury in vitro, and a sepsis mouse model was established via the cecum ligation and perforation method. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was performed for cell apoptosis evaluation. RNA and protein levels were examined by RT-qPCR and western blotting, respectively. Additionally, cell permeability and intestinal mucosa permeability were measured. ELISA was utilized to detect inflammatory cytokine production. H&E staining was conducted for histologic examination of the intestine. Luciferase reporter and RNA pull-down assays were employed to verify the interaction between GAS5, miR-223-3p, and FBXW7. The results showed that GAS5 was downregulated in LPS-exposed NCM460 cells as well as the intestine of septic mice. GAS5 overexpression mitigated LPS-triggered intestinal epithelial cell damage and apoptosis in vitro and reduced pathological damage, inflammation, and intestinal hyperpermeability in septic mice. GAS5 upregulated FBXW7 by interacting with miR-223-3p. Depletion of FBXW7 reversed the protective effects of GAS5 overexpression in vitro. Additionally, GAS5 overexpression inactivated NF-κB signaling in LPS-stimulated NCM460 cells. NF-κB inactivation exerted effects in septic mice similar to those observed with GAS5 overexpression. In conclusion, GAS5 ameliorates sepsis-triggered intestinal barrier disruption by mediating the miR-223-3p/FBXW7 axis and inactivating NF-κB signaling. © 2025 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Interstitial lung diseases (ILDs) encompass a diverse group of pulmonary disorders, with progressive fibrosis leading to poor prognosis. Here we aimed to identify key molecules involved in progressive fibrosis across various ILDs, using spatial transcriptomics (ST). ST analysis (Visium) was performed on lung cryobiopsy specimens from five patients with various ILDs. Two cases, rich in young fibrotic lesions, as defined by fibroblastic foci and destructive alveolar organization, were selected for spatial high-dimensional weighted gene coexpression network analysis (hdWGCNA) to identify key gene networks with biological significance in active fibrosis. We utilized public single-cell RNA sequencing datasets of various ILDs, performed enrichment analysis and trajectory-based differential expression analysis, and quantified cell–cell communication to evaluate the involvement of the spatially extracted module in fibrosis. Immunohistochemical staining of the extracted molecules was performed. Using hdWGCNA, we identified a distinct gene module (the SM2 module) enriched in young fibrotic lesions. The SM2 module was characterized by distinct features of fibroblast activation that were represented across various lesions. Key hub genes within this module, including COL1A2, COL3A1, COL1A1, and SPARC, formed a robust coexpression network. Immunohistochemical staining showed that SPARC, a component of the SM2 module, was highly expressed in young fibrotic lesions, but not in old scarring lesions, across various ILDs. To assess the prognostic significance of SPARC immunohistochemical expression, we extended our analysis to a cohort of 71 patients with unclassifiable ILDs (uILDs), a particularly heterogeneous subtype with unclear pathogenesis and limited treatment options. Higher SPARC levels in the upper, lower, or both lung lobes in uILD were significantly associated with poor overall survival. In summary, an integrated cross-disease approach using ST revealed key gene expression patterns central to active fibrosis and successfully identified SPARC as a potentially beneficial prognostic marker. © 2025 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 nucleolus is a membrane-less body present in the nucleus of the cell. The nucleolus is mainly involved in ribosomal RNA (rRNA) transcription and ribosome biogenesis for protein translation. During cancer formation, nucleolar morphology is altered, and many nucleolar proteins are expressed at a higher level, leading to enhanced ribosome biogenesis and protein translation, which supports cancer aggressiveness, proliferation, migration, and invasion. In this study, we investigated the association of two nucleolar proteins, nucleophosmin (NPM1), and fibrillarin (FBL), with prostate cancer (PCa) aggressiveness and progression. We investigated their cellular localization and expression in different PCa patient tissue specimens and their role in regulating proliferation, migration, invasion, and nucleolar morphology. Our results indicate that NPM1 and FBL are present in the nucleolus of both PCa and noncancerous prostatic cells. The expression of NPM1 and FBL was enhanced in aggressive castration-resistant PCa (CRPC) and neuro-endocrine PCa (NEPC) patient specimens compared to hormone-naïve PCa (HNPC) patient specimens. The expression of NPM1 was enhanced in high-Gleason score PCa compared to low-Gleason score PCa. Silencing of NPM1 and FBL significantly reduced the proliferation, migration, and invasion of PCa cells without affecting noncancerous prostatic cells. Silencing of NPM1 and FBL also changed the morphology of nucleoli in both PCa and noncancerous prostatic cells, where NPM1 silencing fragmented the nucleoli and FBL silencing condensed the nucleoli. Our results suggest that NPM1 and FBL expression correlates with PCa aggressiveness and PCa cells may exhibit a unique dependence on NPM1 or FBL for PCa progression. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Chondroitin sulfate proteoglycan 4 (CSPG4) is a promising target for melanoma immunotherapy, but its expression in benign melanocytic lesions and its diagnostic value remain unexplored. This study assessed CSPG4 expression in benign nevi (BN), dysplastic nevi (DN), and superficial spreading melanomas (SSM), comparing it with PRAME (PReferentially expressed Antigen in MElanoma) and evaluating the cell division cycle 7-related protein kinase (CDC7) and the proliferation marker Ki67. Histological sections were stained using automated instruments, digitized, and analyzed using QuPath. Cohorts of BN, DN, and SSM were created, and positive cells/mm² and H-scores were determined. A total of 336 IHC stainings from 84 specimens were analyzed. CSPG4 expression was readily detected in SSM and was significantly stronger in DN (p = 0.005), with the highest intensity observed in BN (p < 0.001). PRAME showed the highest density of positive cells/mm² in SSM, was significantly reduced in DN (p < 0.001), and was lowest in BN (p < 0.001). Ki67 expression was strong in SSM, moderate in DN (p = 0.62), and low in BN (p = 0.008). CDC7 expression was most intense in DN, less in SSM (p = 0.39), and weakest in BN (p = 0.002). ROC AUC values for SSM versus DN and SSM versus BN were 0.764 and 0.921 for CSPG4, 0.85 and 0.889 for PRAME, 0.735 and 0.742 for Ki67, and 0.425 and 0.767 for CDC7. While PRAME was the most reliable marker for differentiating DN and SSM, CSPG4 was superior for distinguishing BN from SSM due to its high expression in BN. However, CSPG4-targeting therapies may trigger on-target/off-tumor effects due to its high expression in melanocytic nevi. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

In lung squamous cell carcinoma (LUSC), the proportion of exhausted CD8⁺ T cells is considerably higher than in lung adenocarcinoma (LUAD). The exhaustion of CD8⁺ T cells is responsible for the failure of immunotherapies, as terminally exhausted CD8⁺ T cells do not respond to immune checkpoint blockade. Therefore, investigating the regulatory mechanisms underlying CD8⁺ T-cell exhaustion in LUSC is essential for potentiating the efficacy of immunotherapy in this context. In our study, cellular assays revealed that elevated expression of GOT2 in LUSC reinforced the exhaustion of cocultured CD8⁺ T cells, as evidenced by elevated levels of TIGIT and TIM-3, while simultaneously impairing tumor-killing capabilities, as indicated by reduced LDH activity and diminished apoptosis. Animal experiments confirmed that knockdown of GOT2 effectively curbed tumor growth and boosted the CD8⁺ T cell infiltration and tumor-killing function. Mechanistic studies demonstrated that BIRC3, acting as an E3 ubiquitin ligase, can recognize the 366–372 sequence of GOT2, mediating its ubiquitination and degradation. The deficiency of BIRC3 in LUSC interrupted ubiquitination and subsequent degradation of GOT2, leading to elevated GOT2 protein levels, which in turn facilitated CD8⁺ T-cell exhaustion and ultimately compromised their antitumor immune responses. Collectively, our findings elucidated the regulatory role of protein ubiquitination in CD8⁺ T cell functionality, highlighting a novel approach to enhance the sensitivity of LUSC to immunotherapy through the intervention of the BIRC3/GOT2 ubiquitination axis. © 2025 The Pathological Society of Great Britain and Ireland.

Emerging evidence shows that N7-methylguanosine (m⁷G) modification and its writers contribute to the development of diverse cancers. However, the role of m⁷G writers in kidney renal clear cell carcinoma (KIRC) remains unclear. In this study we show that the catalytic components of m⁷G writers, METTL1 and BUD23, are overexpressed in advanced KIRC and are associated with worse overall survival. Knockdown of METTL1 or BUD23 inhibited cell proliferation, colony formation, and migration in KIRC cell lines, indicating their oncogenic role in KIRC. Furthermore, we observed that METTL1 and BUD23 expression was negatively correlated with the expression of key tumor suppressor genes commonly dysregulated in KIRC. We observed METTL1-mediated m⁷G methylation in mRNAs expressed by these tumor suppressor genes, indicating that METTL1 may regulate these genes via m⁷G modification. Overall, our study highlights the oncogenic role of METTL1 and BUD23 in KIRC and their potential as prognostic biomarkers and therapeutic targets in KIRC. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Emerging evidence shows that N7-methylguanosine (m⁷G) modification and its writers contribute to the development of diverse cancers. However, the role of m⁷G writers in kidney renal clear cell carcinoma (KIRC) remains unclear. In this study we show that the catalytic components of m⁷G writers, METTL1 and BUD23, are overexpressed in advanced KIRC and are associated with worse overall survival. Knockdown of METTL1 or BUD23 inhibited cell proliferation, colony formation, and migration in KIRC cell lines, indicating their oncogenic role in KIRC. Furthermore, we observed that METTL1 and BUD23 expression was negatively correlated with the expression of key tumor suppressor genes commonly dysregulated in KIRC. We observed METTL1-mediated m⁷G methylation in mRNAs expressed by these tumor suppressor genes, indicating that METTL1 may regulate these genes via m⁷G modification. Overall, our study highlights the oncogenic role of METTL1 and BUD23 in KIRC and their potential as prognostic biomarkers and therapeutic targets in KIRC. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.