The Journal of Pathology最新文献

{"title":"Fibroblast heterogeneity in Peutz–Jeghers syndrome: identifying the polyp-driving subset†","authors":"Takashi Nishina","doi":"10.1002/path.70112","DOIUrl":"10.1002/path.70112","url":null,"abstract":"<p>Peutz–Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in <i>STK11</i>, 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 <i>et al</i> 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 <i>STK11</i> deficiency to epithelial proliferation. The study reveals that <i>Stk11</i> 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 4","pages":"411-415"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786377","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":"Differential FGFR1 copy number status displays unique tumour immune microenvironment in triple-negative breast cancer","authors":"Yike Gao,&nbsp;Fei Yao,&nbsp;Junyi Pang,&nbsp;Tianlin Sun,&nbsp;Changbin Zhu,&nbsp;Shafei Wu,&nbsp;Zhiyong Liang","doi":"10.1002/path.70121","DOIUrl":"10.1002/path.70121","url":null,"abstract":"<p>Fibroblast growth factor receptor 1 (<i>FGFR1</i>) amplification, a significant cancer alteration with both prognostic and therapeutic relevance, lacks a standardized definition. The relationship between <i>FGFR1</i> copy number (CN) variations and tumour microenvironment (TME) characteristics also remains poorly understood. This study defined <i>FGFR1</i> amplification and investigated TME features across <i>FGFR1</i> CN subtypes in triple-negative breast cancer (TNBC) to guide precise treatment. We analysed 182 TNBC tumour specimens. <i>FGFR1</i> CN status was assessed using fluorescence <i>in situ</i> hybridization (FISH). Next-generation sequencing (NGS) was performed on 88 samples to explore biological differences. Immunohistochemical (IHC) results for CD3, CD4, and CD8 along with clinical data were analysed. Samples were categorized into four groups based on the <i>FGFR1/</i>CEN8 ratio and the mean <i>FGFR1</i> signals per cell. Groups 1 (ratio ≥ 2.0, signals ≥ 4.0) and 2 (ratio ≥ 2.0, signals &lt; 4.0) exhibited robust tumour proliferation, increased <i>FGFR</i> signalling, and an immunosuppressive TME. Conversely, group 4 (ratio &lt; 2.0, signals &lt; 4.0) showed significantly enhanced immune cell infiltration (e.g. CD8⁺ T cells, NK cells), supported by elevated CD3⁺/CD8⁺ T-cell densities. Group 3 (ratio &lt; 2.0, signals ≥ 4.0) was heterogeneous: tumours with <i>FGFR1</i> CN ≥ 5 resembled groups 1/2, while those with CN &lt; 5 mirrored group 4. Thus, <i>FGFR1</i> amplification (<i>FGFR1</i>-Amp) was defined as <i>FGFR1/</i>CEN8 ratio ≥ 2.0 or CN ≥ 5.0 (14.29% prevalence, 26/182). Remaining cases were <i>FGFR1</i>-neutral (<i>FGFR1</i>-Neu). Immune profiling revealed that <i>FGFR1</i>-Amp &amp; HER2-low TNBC had reduced immune cell infiltration but heightened oncogenic signalling (including epithelial–mesenchymal transition, angiogenesis) compared with other subgroups. In contrast, <i>FGFR1</i>-Neu tumours, especially HER2-zero, displayed increased immune cell infiltration (NK cells, effector cells), MHC I/II molecules, activation markers, and elevated immune checkpoint expression (e.g. <i>PD-L1</i>, <i>CTLA4</i>, <i>LAG3</i>). This study defines <i>FGFR1</i> amplification in TNBC and characterizes its TME. <i>FGFR1</i>-Amp in HER2-low TNBC correlates with an immunosuppressive environment, potentially hindering HER2-ADC efficacy and suggesting combined <i>FGFR</i> inhibition. Conversely, <i>FGFR1</i>-Neu &amp; HER2-zero tumours with immune activation may respond better to immunotherapy. © 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 4","pages":"507-520"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70121","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910143","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":"Spatial transcriptomics reveals club cell features and strong CLDN18 expression along the mucinous pathway to invasive mucinous adenocarcinoma","authors":"Joon Young Park,&nbsp;Do Yeon Kim,&nbsp;Hyun Jung Lee,&nbsp;Jung Hee Lee,&nbsp;Hae Ryoun Park,&nbsp;Dong Hoon Shin","doi":"10.1002/path.70120","DOIUrl":"10.1002/path.70120","url":null,"abstract":"<p>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 <i>MUC5AC</i>, <i>MUC6</i>, <i>TFF1</i>, <i>TFF2</i>, and <i>CLDN18</i>. 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). <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 4","pages":"497-506"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910299","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":"A transition zone enriched WIF1+ basal cell subtype is associated with benign prostatic hyperplasia","authors":"Rulin Wang,&nbsp;Qizhi Zheng,&nbsp;Mindy K Graham,&nbsp;Ajay Vaghasia,&nbsp;Jianyong Liu,&nbsp;Jordan Gregg,&nbsp;Tracy Jones,&nbsp;Anuj Gupta,&nbsp;Nicole Castagna,&nbsp;Yan Zhang,&nbsp;Kornel Schuebel,&nbsp;Jennifer Meyers,&nbsp;Alyza Skaist,&nbsp;Dixie Hoyle,&nbsp;Jasmine Kung,&nbsp;Jessica Hicks,&nbsp;Alok Mishra,&nbsp;Yuhan Yang,&nbsp;William G Nelson,&nbsp;Angelo M De Marzo,&nbsp;Srinivasan Yegnasubramanian","doi":"10.1002/path.70117","DOIUrl":"10.1002/path.70117","url":null,"abstract":"<p>The cellular composition and disease susceptibilities of the distinct zones of the human prostate remain incompletely understood. Benign prostatic hyperplasia (BPH) is a common condition that causes widespread morbidity and is nearly exclusively localized to the transition zone (TZ). Through extensive single-cell RNA sequencing (scRNA-seq) of benign regions from prostatectomy specimens, we identified a basal cell population expressing <i>WIF1</i>, <i>VCAN</i>, and <i>NRG1</i>, among other genes, that was significantly enriched in the TZ. Analysis of previously published scRNA-seq datasets further confirmed that <i>WIF1</i>⁺ basal cells were significantly enriched in BPH compared with normal prostate. Pathway and cell–cell communication analyses revealed that this basal subtype is associated with programs related to cell proliferation, epithelial–mesenchymal transition, immune regulation, angiogenesis, and hormone response. Together, the molecular signature, zonal distribution, and pathway enrichment suggest that TZ-enriched <i>WIF1</i>⁺ basal cells may contribute to BPH pathogenesis by promoting epithelial and stromal remodeling. © 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 4","pages":"481-496"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917679","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":"SRF fusion genes in myoid soft tissue tumors","authors":"Ariane Sablon,&nbsp;Constance Pirson,&nbsp;Cristina R Antonescu,&nbsp;Jean-Baptiste Demoulin","doi":"10.1002/path.70114","DOIUrl":"10.1002/path.70114","url":null,"abstract":"<p>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 <i>SRF</i> have long appeared absent in human neoplasms. Recently, however, recurrent <i>SRF</i> 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 <i>SRF</i> 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. <i>SRF</i>-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, <i>SRF</i>-rearranged tumors show consistent phenotypic and clinical features, supporting their recognition as a distinct tumor entity, whereas <i>SRF</i> fusions identified in rhabdomyosarcomas and rare isolated cases likely represent separate biological contexts. Understanding <i>SRF</i> 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 4","pages":"416-426"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786350","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":"Pancreatic polypeptide interacts with neuropeptide Y4 receptor to promote hepatocellular carcinoma progression","authors":"Laura Wormser,&nbsp;Sabrina Kojic,&nbsp;Valerie Fritz,&nbsp;Matthias Benkert,&nbsp;Miriam Düll,&nbsp;Maximilian Waldner,&nbsp;Jürgen Siebler,&nbsp;Jonel Trebicka,&nbsp;Claus Hellerbrand,&nbsp;Markus F Neurath,&nbsp;Anja K Bosserhoff,&nbsp;Peter Dietrich","doi":"10.1002/path.70115","DOIUrl":"10.1002/path.70115","url":null,"abstract":"<p>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 <i>Y4R</i> 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 4","pages":"455-467"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786429","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":"Heterozygous germline deletion in Hif3a exacerbates esophageal squamous cell carcinoma development","authors":"Yanli Qian,&nbsp;Runhua Lin,&nbsp;Zhiwei Liu,&nbsp;Bo Huang,&nbsp;Xi Liu,&nbsp;Ruibing Su,&nbsp;Caiwen Du,&nbsp;Chencai Liu,&nbsp;Chenglin Xiao,&nbsp;Xinxin Zhang,&nbsp;Zhihua Zhang,&nbsp;Dongping Tian,&nbsp;Min Su","doi":"10.1002/path.70106","DOIUrl":"10.1002/path.70106","url":null,"abstract":"<p>Germline variations contribute to esophageal squamous cell carcinoma (ESCC) susceptibility. We identified a germline deletion (exons 7–8) in <i>HIF3A</i> in an ESCC family and investigated its functional impact using CRISPR/Cas9-engineered cells and <i>Hif3a</i>-eKO1 mice (heterozygous for exons 7–8 deletion). Multi-omics analysis of <i>Hif3a</i>-eKO1 and WT mice revealed dysregulated pathways in normal esophagus and during 4NQO-induced carcinogenesis, with key biomarkers validated by immunohistochemistry. <i>Hif3a</i> deficiency enhanced ESCC cell proliferation and invasion <i>in vitro</i> and accelerated 4NQO-induced tumorigenesis <i>in vivo</i>, with <i>Hif3a</i>-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 <i>Hif3a</i>-eKO1 compared with WT. Consistently reduced Krt17 expression in <i>Hif3a</i>-eKO1 was confirmed by both esophageal immunohistochemistry and cellular Western blot analyses. During 4NQO-induced carcinogenesis, <i>Hif3a</i> 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 <i>Hif3a</i> 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"270 4","pages":"427-440"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910134","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":"DUCK-Net: automated deep learning segmentation of ductular reactions in murine liver injury captures multicellular niche dynamics from H&E morphology","authors":"Nathalie Feeley,&nbsp;Kai Williams,&nbsp;Caitlin McCaffrey,&nbsp;Daniel Field,&nbsp;Kyle Davies,&nbsp;Hugh Warden,&nbsp;Luke Boulter,&nbsp;Steve Thorn,&nbsp;Tak Yung Man,&nbsp;Wei-Yu Lu,&nbsp;Stephen J Wigmore,&nbsp;Ewen M Harrison,&nbsp;Stuart J Forbes,&nbsp;Ian P Tomlinson,&nbsp;Timothy J Kendall,&nbsp;Rachel V Guest","doi":"10.1002/path.70113","DOIUrl":"10.1002/path.70113","url":null,"abstract":"<p>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 (<i>R</i>²) of 0.88. Moreover, DUCK-Net kinetics strongly correlated with published spatial transcriptomic (Stereo-seq) analysis of the DDC model, demonstrating that H&amp;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). <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 4","pages":"441-454"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910141","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":"Network based approach identifies miR-145-3p as a central regulatory hub associated to the progression from localized to metastatic medullary thyroid carcinoma","authors":"Anna Citarella,&nbsp;Manuela Petti,&nbsp;Zein Mersini Besharat,&nbsp;Caterina Alfano,&nbsp;Elena Splendiani,&nbsp;Sofia Trocchianesi,&nbsp;Sara Cassandro,&nbsp;Martina Chiacchiarini,&nbsp;Claudia Sabato,&nbsp;Francesca Gianno,&nbsp;Tanja Milena Autilio,&nbsp;Martina Brunetti,&nbsp;Giuseppina Catanzaro,&nbsp;Antonella Verrienti,&nbsp;Rossella Elisei,&nbsp;Raffaele Ciampi,&nbsp;Cristina Romei,&nbsp;Maria Grazia Castagna,&nbsp;Silvia Cantara,&nbsp;Vincenzo Marotta,&nbsp;Luciano Pezzullo,&nbsp;Lorenzo Farina,&nbsp;Cosimo Durante,&nbsp;Agnese Po,&nbsp;Elisabetta Ferretti","doi":"10.1002/path.70116","DOIUrl":"10.1002/path.70116","url":null,"abstract":"<p>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 <i>miR-145-3p</i> 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 <i>MYC</i>, <i>PTEN</i>, <i>BCL2</i>, <i>PIK3CA</i>, <i>AKT1</i>, and <i>MAPK7</i>. In MTC cells, simultaneous inhibition of <i>miR-145-3p</i> 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 <i>miR-145-3p</i> that is associated with metastatic progression and highlights the value of network-based approaches in uncovering mechanisms of cancer dissemination. © 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 4","pages":"468-480"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.70116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910233","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":"MrgprD-mediated macrophage polarization drives chemically induced colitis in mice","authors":"Yiping Lv,&nbsp;Lili Xia,&nbsp;Zhao Qiao,&nbsp;Tiantian Li,&nbsp;Min Xu,&nbsp;Meng Kong,&nbsp;Zongxiang Tang,&nbsp;Fengyi Wan,&nbsp;Lei Lan","doi":"10.1002/path.70125","DOIUrl":"10.1002/path.70125","url":null,"abstract":"<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 <i>Mrgprd</i> KO alleviated dextran sodium sulfate (DSS)-induced acute colitis. We found that MrgprD was expressed in colonic macrophages and DSS treatment increased its expression. <i>Mrgprd</i> 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 <i>Mrgprd</i> 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, <i>Mrgprd</i> 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":"270 4","pages":"521-539"},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","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}