The Journal of Pathology最新文献

{"title":"Dedifferentiation in endometrial cancer is associated with HLA-I silencing that may be restored by IFN-γ","authors":"Antonio De Leo,&nbsp;Madison Wickenberg,&nbsp;Marco Grillini,&nbsp;Camelia Alexandra Coadǎ,&nbsp;Pooja Praveen Kumar,&nbsp;Annie Tong,&nbsp;James Key,&nbsp;Hannah Kim,&nbsp;Felix Kommoss,&nbsp;Mark Carey,&nbsp;Yangxin Fu,&nbsp;Claudio Ceccarelli,&nbsp;Giovanni Tallini,&nbsp;Paul LaPointe,&nbsp;Martin Köbel,&nbsp;Cheng-Han Lee","doi":"10.1002/path.70102","DOIUrl":"10.1002/path.70102","url":null,"abstract":"<p>Dedifferentiated endometrial carcinoma occurs when a prognostically favorable low-grade endometrial carcinoma transforms into a highly aggressive undifferentiated carcinoma following genomic inactivation of core SWItch/Sucrose Non-Fermentable (SWI/SNF) complex protein(s). This typically occurs in a microsatellite-instable molecular context. This study aims to identify the immune evasion mechanisms associated with dedifferentiation. Whole-slide immunohistochemistry-based image analysis was used to compare spatial cancer immunophenotypes and human leukocyte antigen class I (HLA-I) expression between the differentiated and undifferentiated components of 14 SWI/SNF-inactivated dedifferentiated endometrial carcinomas. Flow cytometry and <i>in vivo</i> xenograft studies were performed to gain functional insights. Dedifferentiation was associated with changes in spatial cancer immunophenotypes, most frequently from an inflamed immunophenotype in the differentiated component to an excluded immunophenotype in the undifferentiated component, with loss of tumor HLA-I expression, decreased intraepithelial CD8⁺ T-cell, and increased stromal PD-L1⁺ immune infiltrates. Loss of tumor surface HLA-I expression was also observed in the undifferentiated carcinoma from two patient-derived models of dedifferentiated endometrial carcinomas – DDEC1 and DDEC2. By flow cytometry, IFN-γ treatment restored HLA-I expression in DDEC2 (3.5-fold increase, <i>p</i> &lt; 0.05) but not in DDEC1, which harbored inactivating <i>JAK1</i> mutations. In the <i>in vivo</i> xenograft model of DDEC2, intratumoral injection of IFN-γ restored HLA-I expression in the undifferentiated tumors. These findings implicate the loss of tumor HLA-I expression as an immune evasion mechanism acquired during dedifferentiation in a subset of dedifferentiated endometrial carcinomas. More importantly, IFN-γ can restore tumor HLA-I expression, providing a rationale for combining it with immune checkpoint inhibitors in the treatment of this clinically aggressive cancer type. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 3","pages":"317-327"},"PeriodicalIF":5.4,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive genomic profiling of mucosal melanoma reveals novel fusion transcripts and dysregulation of cell-cycle, MAPK, and PI3K pathways","authors":"Matilde Monti,&nbsp;Martina Brigida Romanello,&nbsp;Luca Agnelli,&nbsp;Matteo Orlandi,&nbsp;Luca Bertoli,&nbsp;Sara Picinoli,&nbsp;Irene Pezzali,&nbsp;Giulio Eugenio Mandelli,&nbsp;Daniela Medicina,&nbsp;Giovanni Ribaudo,&nbsp;Adele Busico,&nbsp;Elena Conca,&nbsp;Vilma Pellegrini,&nbsp;Piera Balzarini,&nbsp;Daniele Gallucci,&nbsp;Anna Di Matteo,&nbsp;Davide Lombardi,&nbsp;Claudia Ghigna,&nbsp;Giancarlo Pruneri,&nbsp;Alessandra Gianoncelli,&nbsp;Marzia Rossato,&nbsp;William Vermi","doi":"10.1002/path.70108","DOIUrl":"10.1002/path.70108","url":null,"abstract":"<p>Mucosal melanomas (MMs) are rare, aggressive cancers with poor outcomes and limited response to standard therapies. A significant knowledge gap exists regarding their genomic landscape and corresponding druggable targets. This study explores this issue through a multi-omic analysis, including whole exome-, RNA-, and targeted sequencing, of unique sinonasal mucosal melanoma (SN-MM) cell lines. SN-MM cell lines showed a low tumour mutational burden and low genomic instability, suggesting that their DNA repair mechanisms are largely intact. However, they exhibited a high prevalence of structural variants, likely from catastrophic genomic events. We also found novel, clinically actionable variants, including oncogenic fusion transcripts. Key findings, such as fusion transcripts and single-nucleotide variants, were validated on diagnostic biopsies. Moreover, using a break-apart FISH assay, we identified <i>BRAF</i> rearrangements as recurrent events in MM, supporting their biological relevance. The MAPK pathway was found to have a significant functional role, sustained by variants such as <i>BRAF</i> p.Asn581Ser, <i>NRAS</i> p.Gly12Asp, and the <i>MKRN1</i>::<i>BRAF</i> fusion. This pathway activation was effectively inhibited by the MEK inhibitor trametinib. This genomic and functional profiling unveiled novel molecular hubs in MM. The findings propose that MEK inhibitors may represent a relevant therapeutic option for <i>BRAF</i> fusions and non-V600 <i>BRAF</i> mutant tumours, providing a novel strategy for this challenging disease. Further molecular and functional validation of novel variants, and particularly of <i>BRAF</i> rearrangements, may reveal additional clinically relevant therapeutic targets. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 3","pages":"380-395"},"PeriodicalIF":5.4,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Practical considerations for pathologists when selecting digital pathology systems: an ESDIP guide","authors":"Diana Montezuma,&nbsp;Vincenzo L'Imperio,&nbsp;David Ameisen,&nbsp;Rita Carvalho,&nbsp;Peter Boor,&nbsp;Sara P Oliveira,&nbsp;Nadieh Khalili,&nbsp;Inti Zlobec,&nbsp;Norman Zerbe,&nbsp;Jordi Temprana-Salvador","doi":"10.1002/path.70103","DOIUrl":"10.1002/path.70103","url":null,"abstract":"<p>The implementation of digital pathology (DP) has been reported across academic, public, and private laboratory settings, providing valuable insights into workflow transformation. However, comparatively little guidance exists on how DP systems should be evaluated prior to acquisition and deployment. Given the substantial financial investment and long-term strategic implications of DP infrastructure, a structured and context-aware evaluation process is essential. In this practical guide, developed by the European Society of Digital and Integrative Pathology (ESDIP) https://www.esdipath.org/, we outline a comprehensive approach for the pre-deployment assessment of DP systems. Drawing on collective experience from multiple institutions and supported by relevant literature, we describe key parameters to consider when evaluating the core components of the DP ecosystem: whole slide scanners, image management systems, workstations, storage infrastructure, and laboratory information systems. We highlight methodological differences between large-scale multisite procurement processes and single-institution implementations, emphasising realistic workload testing, interoperability, and long-term scalability. By integrating technical and clinical perspectives, this guide aims to support pathology departments, IT teams, and institutional decision-makers in selecting DP solutions aligned with their specific institutional needs, infrastructure capabilities, and the future integration of computational pathology. © 2026 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 3","pages":"328-341"},"PeriodicalIF":5.4,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EBV status prediction in gastric carcinoma biopsy images using multiple bag instance learning and foundation model in multicenter data","authors":"Haeyoun Kang,&nbsp;Yujin Nam,&nbsp;Dat Ngo,&nbsp;Min-Sun Cho,&nbsp;Wonae Lee,&nbsp;Hyeong-Chan Shin,&nbsp;Yujun Park,&nbsp;Hee Jung An,&nbsp;Hee-Cheol Kim,&nbsp;Nam Hoon Cho,&nbsp;Hyunki Kim,&nbsp;Baek Hwan Cho","doi":"10.1002/path.70105","DOIUrl":"10.1002/path.70105","url":null,"abstract":"<p>Epstein–Barr virus associated gastric carcinoma (EBVaGC) represents a distinct molecular subtype of gastric cancer with prognostic and therapeutic significance. Current diagnostic practice relies on Epstein-Barr virus-encoded small RNA (EBER) <i>in situ</i> hybridization, which is rarely performed on initial biopsy specimens. We developed a deep learning-based diagnostic pipeline that predicts EBV status directly from H&amp;E-stained gastric biopsy slides. Our method incorporates a multiple bag instance learning (MBIL) framework, which groups spatially adjacent tumor patches to address the inherent heterogeneity of biopsy samples and improve predictive performance. A pathology foundation model was employed to distinguish tumor from normal regions with minimal pathologist annotation, enabling robust tumor detection and contributing to downstream model accuracy. The model was trained on 744 biopsy cases from three general hospitals using 5-fold cross-validation and evaluated on an independent external cohort of 157 cases. MBIL-based models consistently outperformed single-bag approaches. The DSMIL-MB model achieved the best performance, with an area under the receiver operating characteristic curve (AUC) of 0.907 ± 0.044 in internal validation and 0.870 in external testing. TransMIL also showed improved performance with MBIL, with external AUC increasing from 0.701 to 0.853. This framework may serve as a practical prescreening tool for EBV status prediction in routine gastric biopsy specimens prior to EBER-ISH testing, supporting preoperative decision-making and facilitating broader implementation of EBV screening in gastric cancer diagnostics. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 3","pages":"357-367"},"PeriodicalIF":5.4,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIM3 as a therapeutic target in anaplastic thyroid cancer: upregulation in M2-like macrophages induced by tumor microenvironment-derived TGFβ1","authors":"Agustina Jaroszewski,&nbsp;Yeon-Sook Choi,&nbsp;Florencia Hellriegel,&nbsp;Wei Zhang,&nbsp;Fernando Carrizo,&nbsp;Dong Eun Song,&nbsp;María Victoria Laborie,&nbsp;Marcelo Ruggieri,&nbsp;Emiliano Peretti,&nbsp;María Victoria Banus,&nbsp;Cinthia Carolina Stempin,&nbsp;Juan Pablo Nicola,&nbsp;Eva Virginia Acosta Rodríguez,&nbsp;Chi-Ping Day,&nbsp;Gabriel Needle,&nbsp;Inés Califano,&nbsp;Constanza Fernanda Ramacciotti,&nbsp;Ramiro Iglesias-Bartolome,&nbsp;Won Gu Kim,&nbsp;Min Ji Jeon,&nbsp;Laura Fozzatti","doi":"10.1002/path.70104","DOIUrl":"10.1002/path.70104","url":null,"abstract":"<p>Thyroid cancer (TC) is the most common endocrine malignancy. While papillary thyroid cancer (PTC) generally has a favorable prognosis, anaplastic thyroid cancer (ATC) is rare but highly aggressive, with limited treatment options, highlighting the urgent need for novel therapeutic targets. Macrophages are a major component of the immune infiltrate in TC, and their abundance is associated with poor prognosis. We recently identified upregulation of the immune checkpoint TIM3 (T-cell immunoglobulin and mucin-domain containing protein 3) on M2-like macrophages both <i>in vitro</i> and in ATC xenografts. In addition, we have shown that transforming growth factor β1 (TGFβ1) promotes macrophage polarization toward an M2-like phenotype. However, the role and clinical significance of TGFβ1 in regulating TIM3 expression in TC-associated macrophages remains unclear. We found that TGFβ1 secreted by ATC cells significantly increased <i>HAVCR2</i> (TIM3) mRNA expression in human monocytes. Analysis of patient samples demonstrated elevated TIM3 expression in both PTC and ATC tissues compared with adenoma and normal thyroid counterparts. Analysis of publicly available single-cell RNA sequencing datasets further showed increased TIM3 expression in T cells from both tumor types. Notably, TIM3 upregulation was also localized to M2-like macrophages within the thyroid tumor microenvironment (TME), and positively correlated with <i>TGFB1</i>/<i>CD163</i> expression, suggesting the involvement of a TGFβ–TIM3 axis in macrophages in TC. Combined targeting of the TIM3 and PD1 pathway in an immunocompetent mouse model of ATC led to a significant reduction in tumor growth. Together, these findings highlight TIM3 as a promising immunotherapeutic target in TC, with the potential to suppress macrophage-mediated pro-tumor activity while enhancing T-cell-driven anti-tumor immunity within the thyroid TME. © 2026 The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 3","pages":"342-356"},"PeriodicalIF":5.4,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vancomycin enriches Parabacteroides goldsteinii in the gut and promotes reconstruction of the hepatobiliary system in cholestasis","authors":"Shu-Hao Hsu,&nbsp;Huey-Huey Chua,&nbsp;Bang-Yu Liou,&nbsp;Ya-Yuan Cheng,&nbsp;Chia-Ray Lin,&nbsp;Ya-Hui Chen,&nbsp;Tzu-Hsien Yang,&nbsp;Shang-Hsin Wu,&nbsp;Daw-Jen Tsuei,&nbsp;Hui-Ling Chen,&nbsp;Mei-Hwei Chang,&nbsp;Yen-Hsuan Ni,&nbsp;Huey-Ling Chen","doi":"10.1002/path.70101","DOIUrl":"10.1002/path.70101","url":null,"abstract":"<p>Impaired bile secretion disrupts the gut microbiome and perpetuates cholestatic liver injury. Vancomycin (VCM) has been shown to improve cholestasis in human patients, but its biological effects remain unclear. This study aimed to investigate the therapeutic effects of VCM on microbiome modulation and the restoration of liver function. VCM was administered in a modified <i>Abcb11</i> knockout (KO) mice model with pre-existing cholestasis to examine its therapeutic effects and microbiome changes. After 2 weeks of treatment, VCM significantly decreased serum bilirubin while maintaining stable transaminase in the KO mice. Three-dimensional imaging of pan-CK expression by immunofluorescence revealed improvement of the disrupted biliary epithelium and interconnected bile duct network, as evidenced by increased coverage and cumulative duct length in the liver. Gene expression and hepatic bile acid profiling demonstrated that VCM enhanced canalicular/sinusoidal bile acid export while repressing bile acid synthesis, with a reduction in tauro-β-muricholic acid, the predominant bile acid in mice, in KO livers. Fecal microbial analysis using next-generation sequencing identified <i>Parabacteroides goldsteinii</i> (PG) as the predominant species after VCM treatment. KO mice fed PG demonstrated improved cholestasis, with significantly reduced direct bilirubin, alkaline phosphatase, total bile acids in serum, as well as fewer reactive ductules in the liver. <i>In vitro</i> culture of ductal organoids suggested that PG directly promoted the growth of cholangiocytes. RNA sequencing results suggested that PG suppressed pro-inflammatory <i>Lyz1</i> (mouse orthologous gene of human <i>LYZ</i>) and <i>Aqp4</i> and increased pro-proliferative <i>Muc6</i> and <i>Chrm3</i>. This study highlights the therapeutic potential of VCM in cholestasis by enriching PG in the gut and improving biliary structures in the liver, identifying PG as a potential probiotic with beneficial effects in cholestasis. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 3","pages":"303-316"},"PeriodicalIF":5.4,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148667899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMARCA4-deficient undifferentiated malignancies in the digestive system: clinicopathological features and prognostic significance with genomic insights from the TCGA cohort","authors":"Yun-Ran Guo,&nbsp;Chang Liu,&nbsp;Xiao Bai,&nbsp;Ke-Chen Li,&nbsp;Jia-Bao Zhao,&nbsp;Kun Lin,&nbsp;Zi-Ting Zhao,&nbsp;Ji-Xuan Lang,&nbsp;Xiao-Han Li,&nbsp;Qi-Jun Wu,&nbsp;Chun-Dong Zhang","doi":"10.1002/path.70107","DOIUrl":"10.1002/path.70107","url":null,"abstract":"<p>Deficiency in SWItch/Sucrose Non-FermenTable (SWI/SNF) related barrier-to-autointegration factor (BAF) chromatin remodeling complex subunit ATPase 4 (SMARCA4) drives aggressive behavior across various undifferentiated malignancies. However, its clinicopathological features, prognostic analysis, and molecular significance in undifferentiated digestive system malignancies, clinically rare and poorly characterized entities, remain incompletely elucidated. This study investigated the clinicopathological characteristics and prognostic significance of a retrospective cohort (<i>n</i> = 43). Immunohistochemistry (IHC) identified SMARCA4 deficiency in 30.2% of undifferentiated malignant tumors of the digestive system. Clinically, SMARCA4 deficiency constituted a significant poor-prognosis predictor, correlating with poorer overall survival [OS; hazard ratio (HR) = 3.054, 95% confidence interval (CI) 1.277–7.306, log-rank <i>p</i> = 0.006] and disease-free survival (DFS; HR = 2.717, 95% CI 1.129–6.539, log-rank <i>p</i> = 0.015), independent of assessed lineage markers or microsatellite status. Integrated analysis of The Cancer Genome Atlas (TCGA) data of digestive system malignancies revealed that <i>SMARCA4</i>-mutated tumors exhibited elevated tumor mutational burden (TMB) and distinct co-mutation patterns. Notably, <i>SMARCA4</i> mutations significantly co-occurred with multiple potentially actionable therapeutic targets, including receptor tyrosine kinases (<i>ERBB2</i>, <i>ERBB3</i>, <i>MET</i>, and <i>RET</i>), DNA damage response genes (<i>BRCA2</i>), and mismatch repair genes (<i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>). Collectively, our findings identified SMARCA4 deficiency as a predictor of poor prognoses in digestive system malignancies, suggesting a distinct genomic context that may inform therapeutic stratification, including targeted and immunotherapeutic approaches, by focusing on these high-frequency co-mutated targets. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 3","pages":"368-379"},"PeriodicalIF":5.4,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking colitis: MrgprD puts macrophages in the driver's seat^†.","authors":"Kolja Pocha, Konstantin Bräutigam","doi":"10.1002/path.70128","DOIUrl":"https://doi.org/10.1002/path.70128","url":null,"abstract":"<p><p>There is increasing evidence to suggest that dysregulated macrophages play an important role in the promotion and maintenance of inflammatory bowel disease (IBD), yet the underlying mechanisms remain unclear. A recent study published by Lv, Xia, Qiao et al in The Journal of Pathology investigated the role of Mas-related G protein-coupled receptor D (MrgprD) as a surrogate for IBD using a dextran sulfate sodium-induced colitis mouse model. Through a series of experiments using Mrgprd knockout mice, the authors demonstrated that MrgprD drives colitis through its expression in macrophages, promoting M1 macrophage polarization via NF-κB signaling. They also showed that colitis was primarily driven by myeloid-specific rather than neuronal-specific MrgprdD expression. Finally, analysis of genomic data from patients with IBD supported the translational relevance of these findings to human disease. However, their findings require further verification. If confirmed, MrgprD could emerge as a promising treatment target. In any case, macrophages are receiving increasing attention, and pathologists may soon need to consider their assessment in their reporting. © 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TP53 mutations orchestrate partial EMT states in oral squamous cell carcinoma: spatially resolved and in vitro preliminary insights into tumour plasticity.","authors":"Rana Alaaeldin Ibrahim, Hong Wan, Raju Kumar, Muy-Teck Teh, Angray Kang, Emma Bailey, Hannah Cottom, Adrian Biddle, Inês Sequeira, Farida Fortune","doi":"10.1002/path.70123","DOIUrl":"10.1002/path.70123","url":null,"abstract":"<p><p>TP53 is the most frequently mutated gene in oral squamous cell carcinoma (OSCC); however, its role in promoting epithelial-mesenchymal transition (EMT) and tumour progression remains unclear, particularly within the context of intra-tumour heterogeneity. We performed multi-regional whole-exome sequencing (WES) on 43 tumour regions from nine OSCC patients, including matched lymph node metastases. p53, epithelial, and mesenchymal markers were assessed by conventional and multiplexed immunofluorescence (MxIF), followed by digital image analysis using HALO software. EMT-associated gene expression was quantified by RT-qPCR. In vitro assays were performed in epithelial cell lines transiently transfected with the hotspot mutant p53R248Q. TP53 mutations were detected in 7 of 9 patients (77.8%), predominantly as missense mutations in the DNA-binding domain. Mutant tumours exhibited strong nuclear and cytoplasmic p53 accumulation, accompanied by reduced E-cadherin and increased vimentin expression. MxIF revealed a higher proportion of partial EMT-like cells (PCK⁺ vimentin⁺) in mutant tumours (p < 0.05). RT-qPCR showed upregulation of VIM, SLUG, ZEB1, and ZEB2 in TP53-mutant tumours. In vitro, p53R248Q expression increased N-cadherin levels, disrupted E-cadherin membrane localisation, and altered F-actin organisation at the junctions, consistent with EMT-associated phenotypic changes. Collectively, our findings suggest that TP53 mutations, particularly p53R248Q, are associated with partial EMT activation in OSCC. These findings highlight a potential link between TP53 mutations and EMT-related changes in OSCC, suggesting that mutant p53 may contribute to tumour phenotypic plasticity. © 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MrgprD-mediated macrophage polarization drives chemically induced colitis in mice.","authors":"Yiping Lv, Lili Xia, Zhao Qiao, Tiantian Li, Min Xu, Meng Kong, Zongxiang Tang, Fengyi Wan, Lei Lan","doi":"10.1002/path.70125","DOIUrl":"https://doi.org/10.1002/path.70125","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is characterized by aberrant immune responses in the gut. Mas-related G protein-coupled receptor D (MrgprD), which is primarily expressed in sensory neurons of the dorsal root ganglia (DRG), is known to promote neuroinflammation. However, its potential role in driving intestinal inflammation remains undefined. Here, we show that systemic Mrgprd KO alleviated dextran sodium sulfate (DSS)-induced acute colitis. We found that MrgprD was expressed in colonic macrophages and DSS treatment increased its expression. Mrgprd global deletion reduced macrophage infiltration in the colon and suppressed their pro-inflammatory M1 polarization following DSS challenge. Using conditional KO mouse lines, we further demonstrate that myeloid-specific Mrgprd deletion conferred stronger protection than its neuronal deletion. This is evidenced by preserved colon length, reduced histopathology scores, improved barrier integrity, and decreased M1 macrophage proportions. Notably, neuron-specific, but not myeloid-specific, Mrgprd KO accelerated intestinal motility under physiological conditions. MrgprD deficiency reduced M1-associated gene expression and suppressed NF-κB signaling activation in both colonic lamina propria cells and bone marrow-derived macrophages (BMDMs), whereas activation of MrgprD by its agonist enhanced these responses in BMDMs. Bioinformatic analysis further supports the involvement of the MRGPRD-NF-κB signaling axis in human IBD. Collectively, our findings identify MrgprD as a novel driver of acute colitis, acting primarily through NF-κB-mediated pro-inflammatory macrophage polarization in the colon. © 2026 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}