The Journal of Pathology最新文献

{"title":"MicroRNA-371-373 cluster and methylome analysis suggests that a subset of 'somatic-type' malignancies arising in germ cell tumors may originate in yolk sac tumor components.","authors":"João Lobo, Nuno Tiago Tavares, Diana Fonseca, Carmen Jerónimo, Rui Henrique, Nicolas Wyvekens, Yiying Yang, Matija Snuderl, Fiona Maclean, Jennifer Gordetsky, Christopher Dm Fletcher, Michelle S Hirsch, Jason L Hornick, Muhammad T Idrees, Katrina Collins, Laura Warmke, Thomas M Ulbright, Andres M Acosta","doi":"10.1002/path.6412","DOIUrl":"https://doi.org/10.1002/path.6412","url":null,"abstract":"<p><p>Somatic-type malignancies (SMs) arising in germ cell tumors (GCTs) are aggressive neoplasms resistant to systemic treatment. Most are diagnosed in metastatic sites after chemotherapy; however, they have also been well-documented in primary testicular GCTs. Historically, SMs were thought to originate in components of teratoma that acquire molecular alterations equivalent to those that characterize their true somatic counterparts. However, recent studies have shown that SMs typically lack the hallmark molecular alterations seen in similar somatic tumors. Additionally, clinicopathologic and molecular data suggest that a subset may derive from yolk sac tumor (YST) rather than teratoma. In this study, we evaluated the relationship between conventional histological types of GCTs and SMs by comparing expression of microRNA (miR)-371-373 and genomic methylation profiles. A total of 96 samples (including multiple paired conventional GCT-SM samples from individual tumors) were assessed for miR-371-373 expression by RT-qPCR and genomic DNA methylation using a clinically validated assay. Expression of miR-371-373 was higher in conventional GCTs than in SMs (considered as a single category encompassing all histological subtypes). However, miR-371-373 expression was heterogeneous among SMs, with significantly higher levels in sarcomatoid YST (SYST) and glandular neoplasms than in other SMs. Genomic DNA methylation analysis showed that SMs (considered as a single category) did not form a distinct cluster. Instead, they grouped into multiple clusters that did not show perfect correspondence with histology and often included conventional GCTs. Genome-wide methylation assessment showed a higher abundance of hypermethylated regions in SMs than in conventional GCTs. Analysis of paired conventional GCT and 'somatic-type' components that did not meet size criteria for SMs dissected from individual tumors demonstrated separation according to histology, suggesting that epigenetic processes play a role in the transition from conventional GCT to 'somatic-type' phenotypes. Gene-level and pathway-level analyses identified MAPK/RAS signaling, mitosis/proliferation, differentiation towards neural tissue/neuroectoderm, epithelial-to-mesenchymal transition, and DNA repair as key differentially regulated processes in components with somatic-type histology, suggesting mechanisms of progression from conventional to 'somatic' phenotypes in GCT. These results support the hypothesis that a subset of SMs derive from YST and suggest that some subtypes (such as SYST) may represent 'intermediate' phenotypes. Additionally, analysis of differentially methylated promoter regions in SM identified genes and biologic processess that may underlie 'somatic tranformation' in GCTs. © 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727143","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":"Multi-omics analyses reveal distinct molecular characteristics and transformation mechanisms of stage I-III micropapillary lung adenocarcinoma.","authors":"Yang Qu, Xiaoli Feng, Hanlin Chen, Fengwei Tan, Anqi Shao, Jiaohui Pang, Qi Xue, Bo Zheng, Wei Zheng, Qiuxiang Ou, Shugeng Gao, Kang Shao","doi":"10.1002/path.6416","DOIUrl":"https://doi.org/10.1002/path.6416","url":null,"abstract":"<p><p>The micropapillary (MIP) pattern is a high-grade histological subtype of lung adenocarcinoma (LUAD) with poor prognosis. In this study, surgically resected tumor samples from 101 patients with stage I-III MIP-LUAD (MIP ≥30%) were microdissected to separate MIP components from non-MIP components, all of which underwent RNA and DNA whole-exome sequencing (WES). The genomic and transcriptomic landscapes of MIP and non-MIP components within MIP-enriched tumor tissues demonstrated remarkable similarities, notably marked by high epidermal growth factor receptor (EGFR) alteration frequencies. However, when compared to MIP-naïve LUAD tissues, MIP components showed higher chromosomal instability and revealed 18 enriched alterations, encompassing EGFR mutations, EGFR amplifications, and CDKN2A/CDKN2B deletions, which all linked to upregulation of cell proliferation pathways and downregulation of immune pathways. Shared mutations were observed in 97.8% (91/93) of patients with paired DNA WES data for MIP and non-MIP components within the same tissues, suggesting a common origin. The recurrence-free survival analysis identified MACF1, PCLO, ADGRV1, and Fanconi Anemia pathway mutations as negative indicators. In all, we conducted an in-depth analysis of the molecular characteristics and transformation mechanisms of MIP-LUAD, employing microdissection techniques to investigate the genomic and transcriptomic levels within a substantial cohort, providing insights for precision medicine of this aggressive cancer subtype. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727145","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":"A breast cancer PDX collection enriched in luminal (ER⁺) tumors and young premenopausal patients to identify new therapeutic strategies for high-risk patients^†.","authors":"Paola Defilippi, Francesca Nigrelli, Pietro Arina, Daniela Taverna, Vincenzo Salemme","doi":"10.1002/path.6418","DOIUrl":"https://doi.org/10.1002/path.6418","url":null,"abstract":"<p><p>Breast cancer includes a group of neoplasms originating from mammary gland epithelial cells caused by a variety of genetic alterations, with different responses to treatments and outcomes. In clinical practice, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression guides the distinction between luminal A (ER⁺, PR⁺, HER2^-), luminal B (ER⁺, PR⁺, HER2^+/-), and triple-negative (ER^-, PR^-, HER2^-), each with a distinct biological behavior and clinical and therapeutic implications. Approximately 11% of breast cancers are diagnosed in young premenopausal women aged 20-49 years. Patient-derived xenografts (PDXs) offer a powerful solution to integrate personalized medicine and novel therapeutic agents. Dr Belletti's group recently developed a PDX biobank composed of 26 PDX lines highly enriched in luminal A and B and young premenopausal breast cancer patients. The bank faithfully recapitulates the characteristics of the original tumors. A major focus of their research was to exploit these PDXs to assess the resistance to CDK4/6 inhibitors (CDK4/6i), which are critical in managing advanced luminal breast cancers. Their effort addresses a significant gap in existing PDX models, which are limited for these patient subgroups, thereby enabling deeper insights into tumor biology and therapeutic responses in these understudied populations. © 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717638","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":"Phosphodiesterase 5 inactivation in vascular smooth muscle cells aggravates aortic aneurysm and dissection.","authors":"Yuyao Feng, Yunfei Xue, Xiaohang Feng, Zhiwei Li, Luxia Ren, Wenjun Guo, Yangfeng Hou, Ting Shu, Wensi Zhang, Yang Yang, Yitian Zhou, Kai Song, Jiang Xiong, Bao Liu, Jing Wang, Hongmei Zhao","doi":"10.1002/path.6411","DOIUrl":"https://doi.org/10.1002/path.6411","url":null,"abstract":"<p><p>Aortic aneurysm and dissection (AAD) are vascular disorders with high mortality. Previous evidence has suggested an elevated risk of AAD associated with the use of phosphodiesterase 5A (PDE5A) inhibitors. PDE5A, a cGMP-hydrolyzing enzyme, is enriched in vascular smooth muscle cells (SMCs), but the role of SMC-specific PDE5A in the pathogenesis of AAD is still unclear. In this study, PDE5A expression in human and mouse aortic tissues was analyzed by single-cell RNA sequencing (scRNA-seq), western blotting, immunofluorescence, and immunohistochemistry staining. SMC-specific PDE5A knockout (PDE5A^SMC-/-) and PDE5A-overexpressing (PDE5A^SMC-OE) mice were constructed and utilized, along with an AAD mouse model induced by a high-fat diet and angiotensin II (Ang II) infusion. In vivo imaging and histological analyses were performed to assess aortic pathologies. PDE5A expression was reduced in human and mouse AAD aortic tissues, primarily in SMCs. Pharmacological inhibition or genetic knockout of PDE5A in SMCs exacerbated aortic wall dilatation and elastin fiber degradation, increasing AAD incidence. In contrast, the AAD phenotype was rescued in challenged PDE5A^SMC-OE mice. Mechanistically, PDE5A expression influenced myosin light chain (MLC) phosphorylation, a key regulator of SMC contractility. In AAD tissues from PDE5A^SMC-/- mice, increased cGMP-dependent protein kinase (PKG) activation and decreased MLC phosphorylation indicate enhanced aortic relaxation. In conclusion, our findings suggest that PDE5A downregulation or inhibition plays a causative role in exacerbating AAD likely by potentiating cGMP/PKG-mediated aortic SMC relaxation. Our findings highlight the need for caution in the clinical use of PDE5 inhibitors in patients at risk of aortic diseases. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717642","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":"Contribution of alterations in peritubular capillary density and microcirculation to the progression of tubular injury and kidney fibrosis.","authors":"Zhengrong Ren, Fang Shao, Shuli Chen, Yanyan Sun, Zhi Ding, Lei Dong, Junfeng Zhang, Yuhui Zang","doi":"10.1002/path.6414","DOIUrl":"https://doi.org/10.1002/path.6414","url":null,"abstract":"<p><p>Peritubular capillary (PTC) rarefaction is a common pathological feature of chronic kidney disease (CKD). The critical function of PTCs in maintaining blood supply for tubular epithelial cells renders PTCs a promising therapeutic target. However, the role of PTC rarefaction in the progression of kidney fibrosis remains elusive. In this study, we first characterized mice with altered PTC density. CD31 staining, together with microvascular network perfusion with FITC-labelled albumin and laser speckle contrast imaging, revealed a significant increase in PTC density in Flt1 heterozygous-deficient mice, whereas homozygous disruption of the plasminogen activator, urokinase receptor gene (Plaur/uPAR), led to a notable decrease in PTC density. Using these genetically distinct mice, we showed that preexisting higher PTC density protected against tubular injury and attenuated the progression of tubulointerstitial fibrosis in two distinct kidney injury models, namely, ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO). By contrast, Plaur-deficient mice with established lower PTC density displayed exacerbated tubular injury and renal fibrosis when subjected to IRI or UUO. The pathophysiological significance of PTC density was associated with protective effects on tubular cell apoptosis and concomitant regeneration. Finally, vasodilation of the renal capillary with minoxidil, a clinically available drug, effectively prevented UUO-induced tubular injury and renal fibrosis. Moreover, minoxidil treatment abolished the detrimental effect of Plaur deficiency on the UUO-treated kidney, thus suggesting a causative role of PTC density in the susceptibility of Plaur knockout mice to tubular injury following fibrosis. Our results provide an overview of the pathologic significance of PTC density alterations in the progression of CKD, and show that improving peritubular microcirculation is effective in preventing tubular injury and the subsequent renal fibrosis. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655709","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":"Cancer-associated fibroblast heterogeneity in chordoma^†.","authors":"Jack C Henry, Angus J M Cameron","doi":"10.1002/path.6420","DOIUrl":"https://doi.org/10.1002/path.6420","url":null,"abstract":"<p><p>In solid tumours, malignant cells develop relationships with nonmalignant stromal cells to support tumour growth, tissue structure, and nutrient supply. In a recent issue of this journal, Zheng and Guo catalogue the cellular landscape in chordoma using a combination of single-cell and spatial transcriptomics. Despite the mesenchymal nature of chordoma, malignant cells retain expression of epithelial markers, in addition to mesenchymal, partial-EMT, and stem-cell signatures. Cancer-associated fibroblasts (CAFs) are among the most abundant stromal cells and the authors define an inflammatory CAF subtype (iCAF), which is associated with poor outcome and tumour invasion. It is proposed that iCAFs arise from normal fibroblasts during malignant tumour progression and play a causative role in driving an invasive poor prognosis tumour phenotype. Recent reports by this and other groups have separately catalogued cell populations, including CAFs and immune cells in chordoma. The next challenge will be to integrate findings from these distinct studies to allow a consensus to be reached regarding cellular heterogeneity within chordoma, and to allow comparison of CAF populations with those found in other tumour types. Comparison of CAF functions in these predominantly mesenchymal tumours with epithelial solid tumours may reveal interesting lessons about the diverse phenotypes CAFs can bring to distinct tumour ecosystems. Understanding the role of CAFs in chordoma progression may also lead to therapeutic opportunities, but separation of correlation and causation in CAF regulation of tumour phenotypes remains a significant challenge. © 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.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633290","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":"Thrombospondin-1 binds to integrin β3 to inhibit vascular calcification through suppression of NF-κB pathway.","authors":"Fang Liu, Qingchun Liang, Li Li, Yuan Gong, Mingxi Li, Liyun Feng, An Chen, Yuanzhi Ye, Zirong Lan, Yining Li, Jing-Song Ou, Lihe Lu, Jianyun Yan","doi":"10.1002/path.6417","DOIUrl":"https://doi.org/10.1002/path.6417","url":null,"abstract":"<p><p>Vascular calcification is an important risk factor related to all-cause mortality of cardiovascular events in patients with chronic kidney disease (CKD). Vascular extracellular matrix (ECM) proteins have been demonstrated to regulate vascular calcification. ECM protein thrombospondin 1 (THBS1/TSP-1) plays a critical role in the regulation of vascular diseases. However, whether THBS1 is involved in vascular calcification in CKD patients remains unclear. In this study, RNA sequencing datasets from the Gene Expression Omnibus (GEO) database GSE146638 showed that THBS1 was upregulated in the aortas of CKD rats. Enzyme-linked immunosorbent assay (elisa) revealed that serum THBS1 levels were increased in CKD patients with thoracic calcification. Western blotting and immunofluorescence analysis showed that THBS1 expression was increased in calcified vascular smooth muscle cells (VSMCs) and arteries. THBS1 knockdown exacerbated rat VSMC calcification induced by high phosphorus and calcium, as shown by Alizarin red staining and calcium content assays. Conversely, THBS1 overexpression attenuated VSMC calcification and abdominal aortic calcification in rats with CKD. Moreover, addition of recombinant THBS1 protein inhibited calcification of VSMC_S and human arterial rings. Smooth muscle cell-specific knockout of THBS1 mice treated with vitamin D3 displayed aggravated aortic calcification. Mechanistically, the protein-protein interaction database STRING (http://string-db.org/) analysis and coimmunoprecipitation assays revealed THBS1 bound to integrin β3. Reduction of integrin β3 levels abrogated the protective effect of THBS1 on vascular calcification. RNA-seq analysis revealed that THBS1 overexpression modulated the nuclear factor-kappa B (NF-κB) signaling pathway. Of note, the inhibitory effect of THBS1 overexpression on the NF-κB signal was abolished by knockdown of integrin β3. In conclusion, THBS1 interacts with integrin β3 to inhibit vascular calcification through suppression of NF-κB signal, suggesting a promising therapeutic target for vascular calcification in CKD. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623058","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":"Interleukin-11 expressed in the polyp-enriched fibroblast subset is a potential therapeutic target in Peutz-Jeghers syndrome.","authors":"Eva Domènech-Moreno, Wei-Wen Lim, Melissa G Montrose, Myriam Sévigny, Anders Brandt, Toni T Lemmetyinen, Emma W Viitala, Tomi P Mäkelä, Stuart A Cook, Saara Ollila","doi":"10.1002/path.6408","DOIUrl":"https://doi.org/10.1002/path.6408","url":null,"abstract":"<p><p>Peutz-Jeghers syndrome (PJS) is associated with early-onset gastrointestinal polyposis caused by hereditary inactivating pathogenic variants in the tumor suppressor gene STK11 (LKB1). Due to lack of prophylactic therapies, management of PJS polyps requires frequent surveillance. Interestingly, studies in mouse models have revealed that stromal cells drive the polyp formation, but detailed understanding of the cell types and interactions involved has been lacking. Using single-cell RNA sequencing of PJS mouse model polyps, we here identify a polyp-enriched crypt top fibroblast (pCTF) cluster characterized by a transcriptional signature also enriched in PJS patient polyps. The pCTF signature was also noted in primary fibroblasts in vitro following acute STK11 loss. Targeted deletion of Stk11 in crypt top fibroblasts using Foxl1-Cre led to upregulation of the pCTF signature genes and later to polyposis. pCTFs displayed similarity to inflammation-associated fibroblasts, and polyposis was exacerbated by inflammation. Cell-cell communication analysis identified interleukin 11 (IL-11) as a potential pCTF inducer, and consistent with this, IL-11 was required for fibroblast reprogramming toward pCTFs following STK11 loss. Importantly, a neutralizing IL-11 antibody efficiently reduced polyp formation in a PJS model indicating a key, targetable role for IL-11 in polyp development. Together the results characterize pCTFs as a PJS polyp-enriched fibroblast subset and identify IL-11 as a key mediator of fibroblast reprogramming and a potential therapeutic target in PJS. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603092","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":"List of Reviewers 2024","authors":"","doi":"10.1002/path.6404","DOIUrl":"https://doi.org/10.1002/path.6404","url":null,"abstract":"&lt;p&gt;The high quality of manuscripts published in &lt;i&gt;The Journal of Pathology&lt;/i&gt; largely relies on the standards set by our expert reviewers. &lt;i&gt;The Journal of Pathology&lt;/i&gt; 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).&lt;/p&gt;&lt;p&gt;Andres Acosta, Indiana University School of Medicine, Indianapolis, IN, USA.&lt;/p&gt;&lt;p&gt;Alejandro Adam, Albany Medical College, Albany, NY, USA.&lt;/p&gt;&lt;p&gt;Michael Adu-Gyamfi, Charite - Universitätsmedizin Berlin, Berlin, Germany.&lt;/p&gt;&lt;p&gt;Arturo Aguilar-Rojas, Facultad de Ciencias, UNAM, México.&lt;/p&gt;&lt;p&gt;Sarah Aitken, University of Cambridge, Cambridge, UK.&lt;/p&gt;&lt;p&gt;Rita Alaggio, Università degli Studi di Padova, Padova, Italy.&lt;/p&gt;&lt;p&gt;Erik Alexander, Brigham and Women's Hospital, Boston, MA, USA.&lt;/p&gt;&lt;p&gt;Hana Algul, Klinikum rechts der Isar der Technischen Universität München, München, Germany.&lt;/p&gt;&lt;p&gt;Malcolm Alison, Barts and the London School of Medicine &amp; Dentistry, London, UK.&lt;/p&gt;&lt;p&gt;Catherine Alix-Panabieres, CHU de Montpellier, Montpellier, France.&lt;/p&gt;&lt;p&gt;Francisco Javier Alonso, Instituto de Salud Carlos III, Madrid, Spain.&lt;/p&gt;&lt;p&gt;Yoshitsugu Aoki, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan.&lt;/p&gt;&lt;p&gt;Dan Arking, Johns Hopkins School of Medicine, Baltimore, MD, USA.&lt;/p&gt;&lt;p&gt;Gavin Arno, UCL, London, UK.&lt;/p&gt;&lt;p&gt;Christoph Arolt, University of Cologne, Köln, Germany.&lt;/p&gt;&lt;p&gt;Naoko Asano, Nagano Prefectural Shinshu Medical Center, Suzuka, Japan.&lt;/p&gt;&lt;p&gt;Matias Avila, University of Navarra, Pamplona, Spain.&lt;/p&gt;&lt;p&gt;Ruchi Bansal, University of Twente, Twente, Netherlands.&lt;/p&gt;&lt;p&gt;Javier Barallobre-Barreiro, King's College London, London, UK.&lt;/p&gt;&lt;p&gt;Holly Barker, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.&lt;/p&gt;&lt;p&gt;Alexis Barr, Imperial College London, London, UK.&lt;/p&gt;&lt;p&gt;Ali Bashashati, British Columbia Cancer Agency, Vancouver, BC, Canada.&lt;/p&gt;&lt;p&gt;Ömer Bayrak, Yeditepe Universitesi Tip Fakultesi, Istanbul, Turkey.&lt;/p&gt;&lt;p&gt;Carmen Berasain, CIMA Universidad de Navarra, Pamplona, Spain.&lt;/p&gt;&lt;p&gt;Alvaro Berbis, Autonomous University of Madrid, Madrid, Spain.&lt;/p&gt;&lt;p&gt;Helga Bergholtz, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.&lt;/p&gt;&lt;p&gt;Justin A. Bishop, UT Southwestern Medical Center, Dallas, TX, USA.&lt;/p&gt;&lt;p&gt;Cherie Blenkiron, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand.&lt;/p&gt;&lt;p&gt;Karen Blyth, Beatson Institute for Cancer Research, Glasgow, Scotland, UK.&lt;/p&gt;&lt;p&gt;Peter Boor, University Hospital RWTH Aachen, Aachen, Germany.&lt;/p&gt;&lt;p&gt;Jan Bornschein, John Radcliffe Hospital Department of Gastroenterology, Oxford, UK.&lt;/p&gt;&lt;p&gt;Jaime Bosch, Department for BioMedical Research (DBMR), Bern, Switzerland.&lt;/p&gt;&lt;p&gt;Yanis Boumber, University of Alabama at Birmingham, Birmingham, AL, USA.&lt;/p&gt;&lt;p&gt;Chloe Brady, The University of Manchester, Manchester, UK.&lt;/p&gt;&lt;p&gt;Andrea Brancaccio, Istituto di Scienze e Tecnologie Chimiche Rome, Rome, Italy.&lt;/p&gt;&lt;p&gt;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, Julia Kolarova, Julia Vogt, Amanda Macamo, Felix Bormann, Helene Kretzmer, Ernst Jan Speel, Joost van den Oord, Christof Schneider, Stephan Stilgenbauer, Jürgen C Becker, Véronique Winnepenninckx, Erik Biessen, Martin Zenke, Anna Kordelia Kurz, Reiner Siebert, Axel Zur Hausen","doi":"10.1002/path.6410","DOIUrl":"https://doi.org/10.1002/path.6410","url":null,"abstract":"<p><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 n = 14 MCC tissues and n = 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). 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":5.6,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}