The Journal of Pathology最新文献

{"title":"List of Reviewers 2024","authors":"","doi":"10.1002/path.6404","DOIUrl":"https://doi.org/10.1002/path.6404","url":null,"abstract":"<p>The high quality of manuscripts published in <i>The Journal of Pathology</i> largely relies on the standards set by our expert reviewers. <i>The Journal of Pathology</i> wishes to thank the following 440 individuals who assisted by reviewing articles for the Journal in 2024 (affiliations shown are those currently held in our system).</p><p>Andres Acosta, Indiana University School of Medicine, Indianapolis, IN, USA.</p><p>Alejandro Adam, Albany Medical College, Albany, NY, USA.</p><p>Michael Adu-Gyamfi, Charite - Universitätsmedizin Berlin, Berlin, Germany.</p><p>Arturo Aguilar-Rojas, Facultad de Ciencias, UNAM, México.</p><p>Sarah Aitken, University of Cambridge, Cambridge, UK.</p><p>Rita Alaggio, Università degli Studi di Padova, Padova, Italy.</p><p>Erik Alexander, Brigham and Women's Hospital, Boston, MA, USA.</p><p>Hana Algul, Klinikum rechts der Isar der Technischen Universität München, München, Germany.</p><p>Malcolm Alison, Barts and the London School of Medicine & Dentistry, London, UK.</p><p>Catherine Alix-Panabieres, CHU de Montpellier, Montpellier, France.</p><p>Francisco Javier Alonso, Instituto de Salud Carlos III, Madrid, Spain.</p><p>Yoshitsugu Aoki, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan.</p><p>Dan Arking, Johns Hopkins School of Medicine, Baltimore, MD, USA.</p><p>Gavin Arno, UCL, London, UK.</p><p>Christoph Arolt, University of Cologne, Köln, Germany.</p><p>Naoko Asano, Nagano Prefectural Shinshu Medical Center, Suzuka, Japan.</p><p>Matias Avila, University of Navarra, Pamplona, Spain.</p><p>Ruchi Bansal, University of Twente, Twente, Netherlands.</p><p>Javier Barallobre-Barreiro, King's College London, London, UK.</p><p>Holly Barker, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.</p><p>Alexis Barr, Imperial College London, London, UK.</p><p>Ali Bashashati, British Columbia Cancer Agency, Vancouver, BC, Canada.</p><p>Ömer Bayrak, Yeditepe Universitesi Tip Fakultesi, Istanbul, Turkey.</p><p>Carmen Berasain, CIMA Universidad de Navarra, Pamplona, Spain.</p><p>Alvaro Berbis, Autonomous University of Madrid, Madrid, Spain.</p><p>Helga Bergholtz, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.</p><p>Justin A. Bishop, UT Southwestern Medical Center, Dallas, TX, USA.</p><p>Cherie Blenkiron, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand.</p><p>Karen Blyth, Beatson Institute for Cancer Research, Glasgow, Scotland, UK.</p><p>Peter Boor, University Hospital RWTH Aachen, Aachen, Germany.</p><p>Jan Bornschein, John Radcliffe Hospital Department of Gastroenterology, Oxford, UK.</p><p>Jaime Bosch, Department for BioMedical Research (DBMR), Bern, Switzerland.</p><p>Yanis Boumber, University of Alabama at Birmingham, Birmingham, AL, USA.</p><p>Chloe Brady, The University of Manchester, Manchester, UK.</p><p>Andrea Brancaccio, Istituto di Scienze e Tecnologie Chimiche Rome, Rome, Italy.</p><p>Konstantin Bräutigam, ","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 4","pages":"532-539"},"PeriodicalIF":5.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554619","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":"The significance of PAX5 in Merkel cell carcinoma","authors":"Emil Chteinberg,&nbsp;Julia Kolarova,&nbsp;Julia Vogt,&nbsp;Amanda Macamo,&nbsp;Felix Bormann,&nbsp;Helene Kretzmer,&nbsp;Ernst Jan Speel,&nbsp;Joost van den Oord,&nbsp;Christof Schneider,&nbsp;Stephan Stilgenbauer,&nbsp;Jürgen C Becker,&nbsp;Véronique Winnepenninckx,&nbsp;Erik Biessen,&nbsp;Martin Zenke,&nbsp;Anna Kordelia Kurz,&nbsp;Reiner Siebert,&nbsp;Axel zur Hausen","doi":"10.1002/path.6410","DOIUrl":"10.1002/path.6410","url":null,"abstract":"<p>Merkel cell carcinoma (MCC) is a highly malignant skin cancer that expresses epithelial-, neuroendocrine-, and lymphoid-associated genes. Here, we focused on B-cell differentiation, which is characterised by the coexpression of PAX5 and TdT. PAX5 is the master regulator of B-cell commitment and is expressed in 65% of MCC cases. Yet little is known about the underlying molecular biology of the frequently reported PAX5 expression in MCC. Multi-omics analyses, including RNA next-generation sequencing, RT-qPCR, immunohistochemistry, and western blotting, were performed to assess PAX5 expression in MCC. Differential DNA methylation analysis at 61,043 PAX5 binding sites in enhancer and promoter elements was performed to detect differences between <i>n</i> = 14 MCC tissues and <i>n</i> = 91 various normal B-cell populations. RNA analysis revealed full-length PAX5 expression in MCC at the transcriptional level using both PAX5 transcription start sites. PAX5 protein expression was found in 40 of 41 MCCs and six out of seven MCC cell lines. DNA methylation array analysis revealed 1,084 hypermethylated loci of enhancer and promoter elements located in PAX5 binding sites in MCC. Of these, 702 loci were associated with 257 genes that are not expressed. The PAX5-associated regulatory elements of these 257 genes were enriched for interferon regulatory factor 4 (IRF4) and SPi-proto-oncogene (SPI1) binding motifs. Neither IRF4 or SPI1 could be detected in MCC on RNA or the protein level. Thus, because of the absence of these transcription factors, we conclude that full-length PAX5 alone cannot induce B-cell differentiation. © 2025 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":"266 1","pages":"81-94"},"PeriodicalIF":5.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6410","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539739","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":"Multiomic spatial atlas shows deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia","authors":"Emily H Green,&nbsp;Subhag R Kotrannavar,&nbsp;Megan E Rutherford,&nbsp;Hannah M Lunnemann,&nbsp;Harsimran Kaur,&nbsp;Cody N Heiser,&nbsp;Hua Ding,&nbsp;Alan J Simmons,&nbsp;Xiao Liu,&nbsp;D Borden Lacy,&nbsp;M Kay Washington,&nbsp;Martha J Shrubsole,&nbsp;Qi Liu,&nbsp;Ken S Lau,&nbsp;Cynthia L Sears,&nbsp;Robert J Coffey,&nbsp;Julia L Drewes,&nbsp;Nicholas O Markham","doi":"10.1002/path.6406","DOIUrl":"10.1002/path.6406","url":null,"abstract":"<p>Colorectal cancer (CRC) is responsible for over 900,000 annual deaths worldwide. Emerging evidence supports pro-carcinogenic bacteria in the colonic microbiome are at least promotional in CRC development and may be causal. We previously showed toxigenic <i>C. difficile</i> from human CRC-associated bacterial biofilms accelerates tumorigenesis in <i>Apc</i>^<i>Min/+</i> mice, both in specific pathogen-free mice and in gnotobiotic mice colonized with a defined consortium of bacteria. To further understand host–microbe interactions during colonic tumorigenesis, we combined single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and immunofluorescence to define the molecular spatial organization of colonic dysplasia in our consortium model with or without <i>C. difficile</i>. Our data show a striking bipartite regulation of Deleted in Malignant Brain Tumors 1 (DMBT1) in the inflamed versus dysplastic colon. From scRNA-seq, differential gene expression analysis of normal absorptive colonocytes at 2 weeks postinoculation showed DMBT1 upregulated by <i>C. difficile</i> compared to colonocytes from mice without <i>C. difficile</i> exposure. In contrast, our spatial transcriptomic analysis showed DMBT1 dramatically downregulated in dysplastic foci compared with normal-adjacent tissue. We further integrated our datasets to generate custom colonic dysplasia scores and ligand-receptor mapping. Validation with immunofluorescence showed DMBT1 protein downregulated in dysplastic foci from three mouse models of colonic tumorigenesis and in adenomatous dysplasia from human samples. Finally, we used mouse and human organoids to implicate WNT signaling in the downregulation of DMBT1 mRNA and protein. Together, our data reveal cell type-specific regulation of DMBT1, a potential mechanistic link between bacteria and colonic tumorigenesis. Published 2025. This article is a U.S. Government work and is in the public domain in the USA. <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":"266 1","pages":"51-65"},"PeriodicalIF":5.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6406","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539738","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":"Afadin loss induces breast cancer metastasis through destabilisation of E-cadherin to F-actin linkage","authors":"Max AK Rätze,&nbsp;Lotte NFL Enserink,&nbsp;Noboru Ishiyama,&nbsp;Sven van Kempen,&nbsp;Christina HJ Veltman,&nbsp;Isaac J Nijman,&nbsp;Wisse E Haakma,&nbsp;Carlos Caldas,&nbsp;René Bernards,&nbsp;Paul J van Diest,&nbsp;Matthias Christgen,&nbsp;Thijs Koorman,&nbsp;Patrick WB Derksen","doi":"10.1002/path.6394","DOIUrl":"10.1002/path.6394","url":null,"abstract":"<p>Afadin is a multimodal scaffolding protein with essential functions in cell–cell adhesion. Although its loss of expression has been linked to breast cancer invasion and metastasis, the underlying mechanisms driving tumour progression upon mutational Afadin (<i>AFDN</i>) loss in breast cancers remains unclear. In the current study we identified a somatic frameshift <i>AFDN</i> mutation (<i>p</i>.Lys630fs) in an invasive breast cancer sample that coincides with loss of Afadin protein expression. Functional studies in E-cadherin-expressing breast cancer cells show that Afadin loss leads to immature and aberrant adherens junction (AJ) formation. The lack of AJ maturation results in a noncohesive cellular phenotype accompanied by Actomyosin-dependent anoikis resistance, which are classical progression hallmarks of single-cell breast cancer invasion. Reconstitution experiments using Afadin truncates show that proper F-actin organisation and epithelial cell–cell adhesion critically depend on the Coiled-Coil domain of Afadin but not on the designated C-terminal F-actin binding domain. Mouse xenograft experiments based on cell lines and primary patient-derived breast cancer organoids demonstrate that Afadin loss induces single-cell lobular-type invasion phenotypes and overt dissemination to the lungs and the peritoneum. In short, Afadin is a metastasis suppressor for breast cancer through stabilisation and maturation of a mechanical E-cadherin to F-actin outside-in link. © 2025 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":"266 1","pages":"26-39"},"PeriodicalIF":5.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6394","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539736","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":"Cellular origins of mucinous ovarian carcinoma","authors":"Nicola S Meagher,&nbsp;Martin Köbel,&nbsp;Anthony N Karnezis,&nbsp;Aline Talhouk,&nbsp;Michael S Anglesio,&nbsp;Andrew Berchuck,&nbsp;Simon A Gayther,&nbsp;Paul PD Pharoah,&nbsp;Penelope M Webb,&nbsp;Susan J Ramus,&nbsp;Kylie L Gorringe","doi":"10.1002/path.6407","DOIUrl":"10.1002/path.6407","url":null,"abstract":"<p>Mucinous ovarian carcinoma (MOC) is a rare histotype of epithelial ovarian cancer. Its origins are obscure: while many mucinous tumours in the ovary are metastases from the gastrointestinal tract, MOC can occur as an ovarian primary; however, the cell of origin is not well established. In this review we summarise the pathological, epidemiological, and molecular evidence for the cellular origins of MOC. We propose a model for the origins of the various tumours of the ovary with mucinous differentiation. We distinguish Müllerian from gastrointestinal-type mucinous differentiation. A small proportion of the latter arise from teratoma and a distinct terminology has been proposed. Other gastrointestinal mucinous tumours are associated with Brenner tumours and arise from their associated benign lesions, Walthard nests. The remaining mucinous tumours develop either through mucinous metaplasia in established Müllerian tumours or with even greater plasticity through gastrointestinal metaplasia of epithelial or mesothelial ovarian inclusions. This model remains to be validated and mechanistically understood and we discuss future research directions. © 2025 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":"266 1","pages":"9-25"},"PeriodicalIF":5.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539737","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":"Should we worry about high-grade pancreatic neuroendocrine tumor progression and alkylating agents?†","authors":"Wenzel M Hackeng,&nbsp;Koen MA Dreijerink,&nbsp;Lodewijk AA Brosens","doi":"10.1002/path.6409","DOIUrl":"10.1002/path.6409","url":null,"abstract":"<p>Predicting metachronous metastases in localized pancreatic neuroendocrine tumors (PanNETs) and improving survival of patients with advanced disease are some of the most important goals in PanNET research. Both are addressed by a study published recently in this journal. First, the results suggest that heterozygous <i>DAXX</i> mutations are already present in tumor cells but only become potentiated after a single massive chromosomal event that causes loss of heterozygosity and biallelic loss of <i>DAXX</i>. Second, the significant finding that the alkylating agent streptozocin may also induce a hypermutator phenotype with aggressive high-grade progression is further explored. The literature on temozolomide and peptide receptor radionuclide therapy-induced and spontaneous high-grade PanNET progression shows that the cause of high-grade progression is likely multifactorial. High-grade progressed PanNETs may show histopathological features normally seen in neuroendocrine carcinomas. Although it is not clear how often alkylating treatment induces progression, increasing evidence suggests that after an initial response, some patients indeed progress due to streptozocin or temozolomide. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 1","pages":"1-4"},"PeriodicalIF":5.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6409","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497749","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":"Tumor immune microenvironment alterations associated with progression in human intraductal papillary mucinous neoplasms","authors":"Kevin T Jamouss,&nbsp;Alexander Ioannis Damanakis,&nbsp;Abigail C Cornwell,&nbsp;Martine Jongepier,&nbsp;Maria A Trujillo,&nbsp;Michael Johannes Pflüger,&nbsp;Ryan Kawalerski,&nbsp;Alexandre Maalouf,&nbsp;Katsuya Hirose,&nbsp;Shalini Datta,&nbsp;Abigail Sipes,&nbsp;Brian A Pedro,&nbsp;Emma Gudmundsson,&nbsp;Naziheh Assarzadegan,&nbsp;Logan Engle,&nbsp;Robert B Scharpf,&nbsp;Satomi Kawamoto,&nbsp;Elizabeth D Thompson,&nbsp;Laura D Wood","doi":"10.1002/path.6402","DOIUrl":"10.1002/path.6402","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses. To improve patient outcomes, early intervention in precursor lesions such as intraductal papillary mucinous neoplasm (IPMN) is crucial. However, early intervention must be balanced against overtreatment of low-risk lesions that are unlikely to progress, underscoring the need to better understand molecular alterations in neoplastic cells and changes in the tumor microenvironment (TME) that drive the progression of IPMNs. In this study, we characterized alterations in the TME of IPMNs as they progressed to high-grade dysplasia, using immunohistochemistry to quantify immune cell density and activation status in more than 100 well-characterized human IPMN samples. Analyses revealed progression to a more immunosuppressive TME in high-grade IPMN compared with low-grade IPMN, characterized by elevated expression of immune checkpoint molecules (PD-L1, TIM3, VISTA), increased density of macrophages, and decreased density of cytotoxic T cells. Intriguingly, the alterations in macrophages were limited to focal regions of high-grade dysplasia, while T-cell alterations affected the entire IPMN. Additionally, elevated VISTA expression was associated with poorer clinical outcome after IPMN resection in an independent cohort. These findings provide important insights into the interplay between the immune microenvironment and IPMN progression, highlighting potential targets to modify the TME for cancer interception. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 1","pages":"40-50"},"PeriodicalIF":5.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497751","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":"Platelet C3G protects from liver fibrosis, while enhancing tumor growth through regulation of the immune response","authors":"Cristina Baquero,&nbsp;Minerva Iniesta-González,&nbsp;Nerea Palao,&nbsp;Cristina Fernández-Infante,&nbsp;Mateo Cueto-Remacha,&nbsp;Jaime Mancebo,&nbsp;Samuel de la Cámara-Fuentes,&nbsp;María Rodrigo-Faus,&nbsp;M Pilar Valdecantos,&nbsp;Angela M Valverde,&nbsp;Celia Sequera,&nbsp;Sara Manzano,&nbsp;Ángel M Cuesta,&nbsp;Alvaro Gutierrez-Uzquiza,&nbsp;Paloma Bragado,&nbsp;Carmen Guerrero,&nbsp;Almudena Porras","doi":"10.1002/path.6403","DOIUrl":"10.1002/path.6403","url":null,"abstract":"<p>Primary liver cancer usually occurs in the context of chronic liver disease (CLD), in association with fibrosis. Platelets have emerged as important regulators of CLD and liver cancer, although their precise function and mechanism of action need to be clarified. C3G (RapGEF1) regulates platelet activation, adhesion, and secretion. Here we evaluate the role of platelet C3G in chemically induced fibrosis and liver cancer associated with fibrosis using genetically modified mouse models. We found that while overexpression of full-length C3G in platelets decreased liver fibrosis induced by chronic treatment with CCl₄, overexpressed C3G lacking the catalytic domain did not, although in both cases platelet recruitment to the liver was similar. In addition, C3G deletion in platelets (PF4-C3GKO mouse model) increased CCl₄-induced liver damage and hepatic fibrosis, reducing liver platelets and macrophages. Moreover, early liver immune response to CCl₄ was altered in PF4-C3GKO mice, with a remarkable lower activation of macrophages and increased monocyte-derived macrophages compared to WT mice. On the other hand, in response to DEN+CCl₄, PF4-C3G WT mice exhibited more and larger liver tumors than PF4-C3GKO mice, accompanied by the presence of more platelets, despite having less fibrosis in previous steps. Liver immune cell populations were also differentially regulated in PF4-C3GKO mice, highlighting the higher number of macrophages, likely with a pro-inflammatory phenotype, present in the liver in response to chronic DEN+CCl₄ treatment. Proteins upregulated or downregulated in platelet-rich plasma from PF4-C3GKO compared to WT mice might regulate the immune response and tumor development. In this regard, enrichment analyses using proteomic data showed changes in several proteins involved in platelet activation and immune response pathways. Additionally, the higher secretion of CD40L by PF4-C3GKO platelets could contribute to their antitumor effect. Therefore, platelet C3G presents antifibrotic and protumor effects in the liver, likely mediated by changes in the immune response. © 2025 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":"265 4","pages":"502-517"},"PeriodicalIF":5.6,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6403","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481849","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 profiling of ANO7 in prostate tissue: links to AR-signalling-associated lipid metabolism and inflammation","authors":"Olli Metsälä,&nbsp;Gudrun Wahlström,&nbsp;Neha Goel,&nbsp;Mitro Miihkinen,&nbsp;Pekka Taimen,&nbsp;Johanna Schleutker","doi":"10.1002/path.6405","DOIUrl":"10.1002/path.6405","url":null,"abstract":"<p>Prostate cancer (PrCa) is highly prevalent in the Western world. Currently, however, there are many unmet needs in PrCa care, for example in distinguishing between clinically significant and indolent cases in early phases of the disease. <i>ANO7</i> is a prostate-specific gene associated with PrCa risk and prognosis, but its exact function in the prostate remains unclear. This study investigates the role of <i>ANO7</i> in benign prostatic epithelium using spatial transcriptomics by examining differences between <i>ANO7</i>-expressing and non-expressing epithelial regions and their corresponding stromal compartments. A total of 18,676 protein-coding genes were assessed from prostatectomy samples collected from patients with localised prostate cancer. In the collected sample cohort, ANO7 exhibited a distinct, heterogeneous, on–off epithelial expression pattern, enabling an in-depth analysis of ANO7-dependent processes. <i>ANO7</i>-positive epithelium was predominantly enriched with luminal epithelial cells and a specific NK cell subtype, CD56bright. In contrast, <i>ANO7</i>-negative regions were characterised by enrichment of club cells, inflammation, and features of proliferative inflammatory atrophy. Gene-set enrichment analysis revealed that <i>ANO7</i> expression is associated with androgen receptor (AR) signalling and lipid metabolism. A detailed analysis of differentially expressed genes identified an ANO7- signature, which consisted of genes co-expressed with <i>ANO7</i> in luminal cells, that demonstrated high consistency in bulk RNA-sequencing (RNA-seq) data. The ANO7-signature was enriched for AR-regulated genes, which highlighted lipid metabolism processes, particularly arachidonic acid metabolism, as a key metabolic feature of the <i>ANO7</i>-positive epithelium. Furthermore, the ANO7-signature demonstrated clinical significance in low-grade PrCa, correlating with a better response to therapy. In summary, these results highlight the potential role of <i>ANO7</i> in regulating lipid metabolism associated with androgen signalling in benign luminal cells and low-grade cancer, reinforcing the hypothesis that <i>ANO7</i> functions as a tumour suppressor. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 4","pages":"518-531"},"PeriodicalIF":5.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466475","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":"PI3 expression predicts recurrence after chemotherapy with DNA-damaging drugs in gastric cancer","authors":"Kenji Harada,&nbsp;Naoya Sakamoto,&nbsp;Takumi Kitaoka,&nbsp;Yuka Nakamura,&nbsp;Ryotaro Kondo,&nbsp;Ryo Morisue,&nbsp;Hiroko Hashimoto,&nbsp;Yusuke Yamamoto,&nbsp;Shoichi Ukai,&nbsp;Ryota Maruyama,&nbsp;Shingo Sakashita,&nbsp;Motohiro Kojima,&nbsp;Kazuaki Tanabe,&nbsp;Hideki Ohdan,&nbsp;Kohei Shitara,&nbsp;Takahiro Kinoshita,&nbsp;Genichiro Ishii,&nbsp;Wataru Yasui,&nbsp;Atsushi Ochiai,&nbsp;Shumpei Ishikawa","doi":"10.1002/path.6400","DOIUrl":"10.1002/path.6400","url":null,"abstract":"<p>Despite recent advances in gastric cancer therapy, chemotherapy resistance and lack of methods for selecting combination regimens remain major problems. Organoids, which provide a culture system that more closely resembles tumor cell organization than traditional cell lines, can be established from surgical specimens with a high success rate and are widely used for drug sensitivity assays. In this study, we aimed to identify a novel biomarker for predicting multidrug resistance using gastric cancer organoids (GCOs). We evaluated 5-fluorouracil or oxaliplatin-resistant GCOs to find novel biomarkers that reflect multidrug resistance in gastric cancer. To examine the resistance mechanisms, RNA-sequencing analysis and <i>ex vivo</i> drug sensitivity testing were performed. The association of biomarkers with patient prognosis and chemotherapy efficacy was evaluated using three original cohorts with a total of 230 cases. The results were also validated with two independent public cohorts and single-cell RNA sequence data. Increased expression of peptidase inhibitor 3 (<i>PI3</i>) was detected in all 5-fluorouracil or oxaliplatin-resistant GCOs. Our findings suggest a potential association of <i>PI3</i> expression with ribosome biosynthesis and RNA metabolism under organoid conditions. We also found that <i>PI3</i> overexpression promoted 5-fluorouracil/oxaliplatin/cisplatin resistance but not paclitaxel resistance. Immunohistochemical evaluation of PI3 expression revealed that the PI3-positive gastric cancer group had a poorer outcome, especially in terms of time to recurrence. PI3 positivity was also an independent predictor of relapse after chemotherapy with DNA-damaging agents. <i>PI3</i> promotes DNA-damaging drug resistance through multiple downstream regulations related to RNA and ribosomal metabolism. <i>PI3</i> may be useful as a biomarker for the therapeutic selection of non-DNA-damaging agents. © 2025 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":"265 4","pages":"472-485"},"PeriodicalIF":5.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466468","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}