The Journal of Pathology最新文献

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is most often caused by cumulative UV exposure. However, cSCC may also arise independently of UV exposure, on sites of sustained skin damage like chronic ulcers, scars, Recessive Dystrophic Epidermolysis Bullosa (RDEB), and inflammatory skin diseases such as hidradenitis suppurativa (HS). Little is known about non-UV-induced skin carcinomas. We aimed to describe the clinical, pathological, and genetic features, of non-UV-induced cSCC. We collected clinical and pathologic data corresponding to 31 patients with non-UV-induced cSCC, including 5 cSCC on HS, 4 on chronic leg ulcers and 8 on RDEB. DNA was extracted from FFPE samples and analysed using a NGS assay targeting 523 cancer genes. A comparison was performed with published genetic data obtained in non-UV-induced and UV-induced cSCC. We found that the Tumour Mutational Burden (TMB) of non-UV-induced cSCC was 6-times lower than the published TMB of UV-induced cSCC. The predominant mutational signature was a clock-wise signature. By comparing the frequency of driver mutations, we found TP53 and NOTCH1 to be significantly less frequently mutated than in UV-mutated cSCC. Interestingly, KMT2B (a histone methyl transferase) was mutated in 11/31 non-UV-induced cSCC and this proportion was significantly higher than in UV-mutated cSCC. These mutations were high impact loss-of-function mutations. We found that knocking down KMT2B expression using siRNA did not affect cell proliferation of SCC-13 and A-431 cell lines, however, it significantly increased cell migration in vitro. Taken together, this study provides a comprehensive description of non-UV-induced cSCC and identifies that KMT2B is mutated and involved in non-UV-induced cSCC carcinogenesis. © 2025 The Pathological Society of Great Britain and Ireland.

Fibrosis is a common end-stage pathway of progressive chronic kidney diseases. Previously we demonstrated that myocardin-related transcription factor (MRTF)–serum response factor (SRF) signaling drives the expression of fibrosis-related molecules through actin cytoskeleton dynamics in renal fibroblasts. However, it has not been elucidated whether actin-associated proteins relate to the pathogenesis of fibrosis. Here, we reveal that the actin cytoskeleton-regulating pathway is significantly correlated with estimated glomerular filtration rate (eGFR) and collagen type 1 alpha 1 expression in human proteome analysis. We found that palladin was one of the TGF-β1-dependent actin-associated proteins in renal fibroblasts. Our mechanistic studies demonstrated that palladin activates MRTF–SRF signaling via actin cytoskeleton rearrangement upon TGF-β1 stimulation. In addition, palladin expression itself was enhanced by MRTF–SRF signaling, indicating a positive feedback loop. In vitro, genetic silencing of the palladin–MRTF–SRF axis suppressed extracellular matrix production and myofibroblast differentiation. In preclinical models in vivo, fibroblast-specific palladin-deficient mice (palladin^iFBKO) were protected from kidney dysfunction and fibrosis that developed in adenine-induced nephropathy, which was associated with reduced numbers of myofibroblasts compared to wild type (palladin^F/F) mice. In patients with renal disease, palladin was significantly upregulated in the renal interstitium of patients with low eGFR and kidney fibrosis. Moreover, upregulation of the palladin–MRTF–SRF axis correlated with kidney function and fibrosis in patients with various kidney diseases, including IgA nephropathy, diabetic nephropathy, and nephrosclerosis. Taken together, we consider palladin to be a novel regulator of actin cytoskeleton signaling in fibrotic fibroblasts and represents a novel therapeutic target for the treatment of progressive kidney diseases. © 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 myeloid leukemia (CML) is a stem cell-driven neoplasia characterized by the expression of the constitutively active tyrosine kinase (TK) BCR/Abl. Under low oxygen, a condition that characterizes stem cell niches (SCNs) in vivo, the oncogenic BCR/Abl_protein is suppressed. Consequently, leukemia stem cells (LSCs) residing within SCNs show resistance to TK inhibitors (TKIs), the first-line therapy for CML, due to the lack of their molecular target. It is therefore important to deepen understanding of the mechanisms driving BCR/Abl_protein suppression to design new strategies able to repress TKI-resistant LSCs. Our previous studies showed that BCR/Abl_protein suppression occurred when glucose approaches completed exhaustion in culture medium. As lactate is the main byproduct of glucose catabolism in low oxygen, in this study we addressed the role of lactate in regulating BCR/Abl_protein expression. We found that treatment of CML cells with 2-DG, which blocks glycolysis and thereby lactate production, or monocarboxylate transporter (MCT) inhibitors, which reduce lactate excretion, enhanced BCR/Abl_protein expression and promoted maintenance of a BCR/Abl-dependent/TKI-sensitive stem cell phenotype. The effects of MCT inhibition were abolished when exogenous lactate was added to culture medium, resulting in the suppression of BCR/Abl_protein expression. Treatment with 3-hydroxy-butyrate acid, an antagonist of the GPR81 plasma membrane ‘lactate’ receptor, prevented lactate-driven BCR/Abl_protein suppression, while the selective GPR81 agonist 3-chloro-5-hydroxy-BA counteracted the maintenance of BCR/Abl_protein induced by MCT inhibition. Our results indicate that GPR81 engagement by extracellular lactate determines BCR/Abl_protein suppression in low oxygen environments. © 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.

Pancreatic cystic lesions present a unique opportunity to identify and potentially prevent pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Until now, research has primarily focused on intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), whose potential for malignant transformation is well established. In recent years, however, a new pathological entity has emerged: the simple mucinous cyst (SMC). SMCs are distinct from other cystic lesions, as they lack both communication with the pancreatic ductal system (a hallmark of IPMNs), and the ovarian-like stroma, characteristic of MCNs. The recent work by Pea et al, published in The Journal of Pathology, suggests that these lesions can progress to PDAC, underscoring the need for further characterization. In this commentary, we review the key findings of this study and discuss the potential next steps required to translate these discoveries into actionable clinical practice. © 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.

Recent advancements in pathological imaging have facilitated single-cell and subcellular-level analysis based on high-resolution images for tumor subtyping, cytomorphological assessment, and infection detection. As high-resolution imaging is often limited by cost, super-resolution methods provide a practical alternative with only low-resolution data. However, existing methods generally suffer from artifacts, oversmoothing, and slow inference speed. In this study, we developed a hierarchal deep learning framework based on local pathological image patterns, named Hierarchical Local Image Patterns (HLIP), to achieve accurate, high-fidelity, and real-time super resolution with flexible magnifications. HLIP integrates semantic features with both pixel- and morphology-level features and reconstructs super-resolution images by the recognized local pathological image patterns. Benchmark analysis showed HLIP achieved the best performance and robustness on both internal and external test datasets. The generated super-resolution images contain abundant pathological details and maintain high fidelity. HLIP can be used for the enhancement of other models across multiple clinical scenarios, including gland segmentation, cell segmentation, Helicobacter pylori detection, and therapy response prediction. With its superior performance in pathology image super resolution, HLIP offers a versatile tool for image preprocessing in computer-aided systems, thereby supporting accurate diagnosis in clinical practice. © 2025 The Pathological Society of Great Britain and Ireland.

Ana-Rita Pedrosa, Alejandro Castillo-Kauil, Yuliia Kravchuk, Louise Reynolds, Bruce Williams, David Moore, Cameron Lang, Srinivas Allanki, Eleni Maniati, Alexandros Hardas, Jozafina Haj, Rebecca Drake, Julie Cleaver, Julie Foster, Jana Kim, Ester Stern, Jane Sosabowski, Gilbert O. Fruhwirth, Erik Sahai, Ori Wald and Kairbaan Hodivala-Dilke. J Pathol 2025; 266: 405–420; https://doi.org/10.1002/path.6435

The senior author has informed the editors of three errors in the Acknowledgements section of this article, first published on 18 June 2025 in Wiley Online Library (wileyonlinelibrary.com).

First, the affiliation of the technicians was given incorrectly. The correct affiliation is HEFCE-funded specialist animal technicians.

Second, the Animal Technician Service (ATS) was stated incorrectly. The correct affiliation is the BCI Animal Technician Service (ATS).

Third, the name of the second technician was spelt incorrectly. The correct spelling is Kaylee O'Brien Perry.

The original sentence read:

“The authors would also like to thank the BSU technicians Julie Holdsworth and Kaylee Perry and the Animal Technician Service (ATS) for their support in all of the mouse studies.”

The corrected sentence should read:

“The authors would also like to thank the HEFCE-funded specialist animal technicians Julie Holdsworth and Kaylee O'Brien Perry, and the BCI Animal Technician Service (ATS), for their support in all of the mouse studies.”

The authors apologise for these errors and for any inconvenience caused.

p53 is one of the most important tumour suppressors exerting antitumour effects primarily via apoptosis. TP53 mutations are common in gastric tumorigenesis; however, nearly half of the gastric cancers (GCs) remain wildtype TP53 (TP53_WT). We investigated epigenetic/genetic profiles of GCs and the carcinogenic mechanisms underlying GCs with TP53_WT. Comprehensive DNA methylation analysis revealed four DNA methylation epigenotypes (MEs) in GCs, namely, high ME (HME), extremely HME (E-HME), low ME (LME), and extremely LME (E-LME). E-HME matched Epstein–Barr virus (EBV)-positive GC (E-HME/EBV). HME can be further categorised into MLH1-deficient (HME_MLH1(−)) and -proficient cases. The Cancer Genome Atlas data confirmed that HME_MLH1(−)/microsatellite instability (MSI) and E-HME/EBV cases significantly retained TP53_WT and had higher MDM2 expression levels than other MEs. We hypothesised that apoptosis pathways in TP53_WT GC may be suppressed post-transcriptionally by activated MDM2. Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA-hypermethylated GC cases, HME_MLH1(−)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway. © 2025 The Pathological Society of Great Britain and Ireland.

Terminal deoxynucleotidyl transferase (TdT) is occasionally expressed in large B-cell lymphoma (LBCL), and this causes difficulty in differential diagnosis from B-lymphoblastic leukaemia/lymphoma (B-ALL/LBL). We reviewed 31 cases of TdT-positive LBCL and B-ALL/LBL, and their final diagnosis included 19 diffuse large/high-grade BCLs with MYC and BCL2 rearrangements (five DLBCL-MYC/BCL2, 14 HGBCL-MYC/BCL2), three DLBCL not otherwise specified (NOS), three HGBCL-NOS, four B-ALL/LBL, and two unclassifiable cases. TdT was variably expressed in all these cases, without any clear demarcation among different groups. Loss or partial loss of CD20 expression was seen in 13/17 DLBCL/HGBCL-MYC/BCL2, 2/3 HGBCL-NOS, and 2/2 unclassified, albeit not in DLBCL-NOS. Expression of BCL6 and/or MUM1 was seen in 3/4 B-ALL/LBLs and 2/2 unclassified. Next-generation sequencing revealed characteristic mutations associated with follicular lymphoma and its high-grade transformation in each DLBCL/HGBCL-MYC/BCL2, and also frequent variants in genes targeted by somatic hypermutation (SHM) in almost all DLBCL/HGBCL-MYC/BCL2, DLBCL-NOS, and HGBCL-NOS but one case. In contrast, such mutations were absent in B-ALL/LBL. There were no pathognomonic mutations in the two unclassifiable cases, although one showed a moderate level of somatic mutations in its rearranged IGHV. Furthermore, in three cases of TdT-positive HGBCL-MYC/BCL2, studies of previous or concurrent follicular lymphoma demonstrated their divergent evolution from an IGH::BCL2-positive cell population following acquisition of MYC translocation. In conclusion, mutation profiling analysis including the SHM target genes is highly valuable in the differential diagnosis between TdT-positive LBCL and B-ALL/LBL. © 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.

Lethal prostate cancer (PCa) is a genetically heterogeneous disease characterized by evolving androgen receptor (AR) signaling, eventually culminating in castration resistance. The tumor suppressor gene BRCA1 has multiple functions that include secondary processes cooperating with its main function as a caretaker of genomic integrity. BRCA1 is often mutated in breast and ovarian cancer, but BRCA1 mutations are also associated with PCa, although they are less frequently observed. Most PCa patients do not, however, carry BRCA1 mutations, and interestingly, it has been shown that BRCA1 expression is enriched in castration-resistant PCa. In this study we elucidated the prostate tissue-specific role of the BRCA1 protein. Although the regulation of DNA damage response genes has been studied in PCa, comprehensive analyses of BRCA1 regulation in the context of androgen signaling are lacking. Our results indicate that BRCA1 is dynamically regulated by AR signaling and that activation of AR via its natural ligand, dihydrotestosterone, represses BRCA1 expression. Our analyses both in vitro and of patient samples and mouse xenografts showed that BRCA1 expression was induced and sustained after androgen deprivation. Moreover, we observed that oxidative stress–related pathways were regulated by BRCA1 in PCa cells and that androgen deprivation therapy–induced activation of BRCA1 supported the function of NRF2, the master regulator of antioxidant defense, and a known interactor of BRCA1. Impaired NRF2 activity, in the absence of BRCA1, decreased growth in a 3D environment. Our findings shed light on the functional role of BRCA1 protein in PCa and suggest that BRCA1 is regulated by the evolving AR signaling state during PCa progression. Thus, AR-mediated suppression of BRCA1 accumulates oncogenic alterations in the early phases of PCa tumor progression and safeguards from excessive reactive oxygen species (ROS) when upregulated during androgen deprivation therapy. © 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.

Coronavirus disease 2019 (COVID-19) is of special concern to patients with chronic obstructive pulmonary disease (COPD), given their susceptibility to exacerbations caused by respiratory tract infections. As the susceptibility of acquiring a SARS-CoV-2 infection in COPD remains unclear, this study explored the airway expression of SARS-CoV-2 entry-associated proteins in the lungs of COPD patients in comparison to non-COPD controls. Immunohistochemical staining of lung tissue was performed to investigate the expression profiles of SARS-CoV-2 entry-associated proteins in the bronchial epithelium of 27 COPD patients and 40 non-COPD controls. In addition, the associations between these expression profiles with lung function in COPD patients and smoking status in non-COPD controls were examined. COPD patients demonstrated smoking-independent lower expression of HSPA5, NRP1, BSG, TMPRSS2, and ITGB6 in airway epithelium as compared to non-COPD controls. No significant differences were observed for Furin, CTSL, ADAM17, and ITGA5. BSG percentage area expression was significantly negatively associated with lung function in COPD patients. Moreover, the study revealed smoking-associated differences for Furin, HSPA5, ADAM17, BSG, ITGA5, and ITGB6 within non-COPD controls, with lower airway epithelial expression (except for Furin) in ever-smokers than in never-smokers. To conclude, this study showed a lower expression of a specific set of SARS-CoV-2 entry-associated proteins in the bronchial epithelium of COPD patients compared with non-COPD controls, while other factors showed similar expression levels. The consequences of these findings on COVID-19 susceptibility remain uncertain. Although reduced expression of entry factors may suggest less cellular availability for viral entry, it could be speculated that the similar expression levels of other factors, together with impaired airway clearance in COPD, may still facilitate infection, thereby providing potential mechanistic insight into COVID-19 susceptibility in this patient population. © 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.