The Journal of Pathology最新文献

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Development and characterisation of improved unifocal primary mouse lung cancer models with metastatic potential 具有转移潜力的改进的单灶原发性小鼠肺癌模型的发展和特征。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-06-18 DOI: 10.1002/path.6435
Ana-Rita Pedrosa, Alejandro Castillo-Kauil, Yuliia Kravchuk, Louise Reynolds, Bruce Williams, David Moore, Cameron Lang, Srinivas Allanki, Eleni Maniati, Alexandros Hardas, Jozafina Haj, Rebecca Drake, Julie Cleaver, Julie Foster, Jana Kim, Ester Stern, Jane Sosabowski, Gilbert O. Fruhwirth, Erik Sahai, Ori Wald, Kairbaan Hodivala-Dilke
{"title":"Development and characterisation of improved unifocal primary mouse lung cancer models with metastatic potential","authors":"Ana-Rita Pedrosa,&nbsp;Alejandro Castillo-Kauil,&nbsp;Yuliia Kravchuk,&nbsp;Louise Reynolds,&nbsp;Bruce Williams,&nbsp;David Moore,&nbsp;Cameron Lang,&nbsp;Srinivas Allanki,&nbsp;Eleni Maniati,&nbsp;Alexandros Hardas,&nbsp;Jozafina Haj,&nbsp;Rebecca Drake,&nbsp;Julie Cleaver,&nbsp;Julie Foster,&nbsp;Jana Kim,&nbsp;Ester Stern,&nbsp;Jane Sosabowski,&nbsp;Gilbert O. Fruhwirth,&nbsp;Erik Sahai,&nbsp;Ori Wald,&nbsp;Kairbaan Hodivala-Dilke","doi":"10.1002/path.6435","DOIUrl":"10.1002/path.6435","url":null,"abstract":"<p>Lung cancer is the leading cause of cancer-related death globally. To better understand the biology of lung cancer, mouse models have been developed using either tail vein-injected tumour cell lines or genetically modified mice. The current gold-standard models typically present with multiple lung foci. However, although these models are widely used, their correlation with human disease are limited, as early-stage human lung cancer usually presents as a single lesion rather than multiple foci. Additionally, a major challenge of using multifocal lung tumour models is the difficulty in distinguishing primary lung tumours from intrathoracic metastasis and lethal levels of lung congestion before distant metastases develop. Here, we present a refined and detailed surgical method in which murine tumour cells [Lewis lung carcinoma (LLC), alveogenic lung carcinoma (CMT), or <i>Kras/Trp53-</i>KP mutant cells] were injected directly into the left lung lobe of C57BL/6 mice, or, alternatively, adenoviral-Cre or adenoviral-FlpO was administered directly into the left lung lobe of <i>Kras</i><sup><i>LSL-G12D</i></sup>;<i>Trp53</i><sup><i>fl/fl</i></sup> or <i>Kras</i><sup><i>FSF-G12D</i></sup>;<i>Trp53</i><sup><i>frt/frt</i></sup> (KP) mice, respectively. This method generated unifocal primary left lung lobe tumours with traceable spread to local and distant sites. A cross-comparison of the unifocal models described commonalties and differences between LLC, CMT, KP cells, and adenoviral-Cre or -FlpO methods in terms of timings for primary lung tumour growth and traceable spread to local and distant sites, histological analysis of CD3 and CD11b immune cell infiltration, and Picrosirius Red analysis of extracellular matrix complexity. Lastly, the frequency of clinical histopathological features typical of human lung cancer were assessed across the unifocal mouse models to provide a direct comparison with human lung cancer. Overall, this study details a refined and reproducible protocol for intralobular lung injection to generate unifocal lung cancer models that resemble key features of human lung cancer. This approach can be applied to other lung cancer initiation strategies. The cross-comparative histological analysis across the models tested here offers a valuable resource to aid researchers in selecting the most appropriate next-generation unifocal lung cancer models for their specific research needs. © 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 4-5","pages":"405-420"},"PeriodicalIF":5.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6435","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324041","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}
引用次数: 0
Soft tissue sarcoma with MN1 gene fusions: a report of three cases with aggressive clinical behavior MN1基因融合软组织肉瘤:3例侵袭性临床表现报告。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-06-12 DOI: 10.1002/path.6441
Carla Saoud, Josephine K Dermawan, Narasimhan P Agaram, Marc Rosenblum, Tejus A Bale, Cristina R Antonescu
{"title":"Soft tissue sarcoma with MN1 gene fusions: a report of three cases with aggressive clinical behavior","authors":"Carla Saoud,&nbsp;Josephine K Dermawan,&nbsp;Narasimhan P Agaram,&nbsp;Marc Rosenblum,&nbsp;Tejus A Bale,&nbsp;Cristina R Antonescu","doi":"10.1002/path.6441","DOIUrl":"10.1002/path.6441","url":null,"abstract":"<p>Canonical <i>MN1</i> fusions with either <i>BEND2</i> or <i>CXXC5</i> gene partners represent the molecular hallmark of astroblastoma, a stand-alone group among central nervous system (CNS) high-grade neuroepithelial tumors based on their distinct methylation profile. Outside the CNS, <i>MN1</i> fusions have been rarely reported, mostly with nonrecurrent gene partners. Herein, we present three cases of soft tissue sarcomas harboring <i>MN1</i> gene rearrangements, two of which had <i>MN1</i> (exon 1)::<i>CXXC5</i> (exon 2) gene fusion and the last had <i>MN1</i> (exon 1)::<i>ZFP64</i> (exon 2) gene fusion. The tumors occurred in young to middle-aged adults (two females and one male) and involved the preauricular, abdominal, and sacral soft tissue. Patients with <i>MN1</i>::<i>CXXC5</i> fusion had widespread metastatic disease at presentation. Histologically, tumors with the <i>MN1</i>::<i>CXXC5</i> fusion showed nests of monomorphic round and focally spindled cells, compatible with round cell sarcoma, while <i>MN1</i>::<i>ZNFP64</i> fused tumors exhibited monomorphic spindle cells arranged in storiform and short fascicular patterns. Mitotic activity was brisk in all cases; however, tumor necrosis was minimal to absent. <i>MN1</i>::<i>CXXC5</i> fused tumors exhibited CD99 and S100 expression, an immunophenotype that is not specific for a particular line of differentiation and is distinct from astroblastoma. <i>MN1</i>::<i>ZNFP64</i> were positive for p63 and androgen receptor (AR) expression. Low tumor mutation burden and low levels of genome alteration were seen in all cases. DNA methylation profiling showed that the three cases could not be classified into any of the current methylation classes using the DKFZ classifier for sarcomas (version 12.2) or CNS tumors (version 12.8). T-distributed Stochastic Neighbor Embedding analysis revealed that the three sarcomas with <i>MN1</i> gene rearrangement clustered together, forming a distinct group, in close proximity to epithelioid sarcoma, separate from CNS high-grade neuroepithelial tumor with <i>MN1</i> alterations. In our series, all three cases exhibited aggressive clinical behavior; notably, the two patients with <i>MN1</i>::<i>CXXC5</i> gene fusion sarcomas succumbed to the disease within 20 to 23 months. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 4-5","pages":"435-446"},"PeriodicalIF":5.6,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273812","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}
引用次数: 0
Post-COVID-19 condition: clinical phenotypes, pathophysiological mechanisms, pathology, and management strategies covid -19后的情况:临床表型、病理生理机制、病理和管理策略。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-06-10 DOI: 10.1002/path.6443
Larissa E Vlaming-van Eijk, Guolu Tang, Arno R Bourgonje, Wilfred F A den Dunnen, Jan-Luuk Hillebrands, Harry van Goor
{"title":"Post-COVID-19 condition: clinical phenotypes, pathophysiological mechanisms, pathology, and management strategies","authors":"Larissa E Vlaming-van Eijk,&nbsp;Guolu Tang,&nbsp;Arno R Bourgonje,&nbsp;Wilfred F A den Dunnen,&nbsp;Jan-Luuk Hillebrands,&nbsp;Harry van Goor","doi":"10.1002/path.6443","DOIUrl":"10.1002/path.6443","url":null,"abstract":"<p>Post-COVID-19 condition (PCC), also known as long COVID, is a complex multiple organ system condition that can develop and persist for months after acute COVID-19. PCC encompasses a wide range of symptoms, resulting in heterogeneous clinical manifestations. These manifestations likely arise from diverse underlying pathophysiological mechanisms, which, in turn, are influenced by risk factors such as age, sex, and comorbidities. To this end, characterising clinical phenotypes of PCC is essential for deepening our understanding of its (potentially) distinct pathophysiological mechanisms and for advancing diagnostic and patient-tailored management strategies. PCC is thought to result from a complex interaction of various pathophysiological mechanisms, leading to functional and structural pathological alterations across multiple organ systems. Investigating these alterations is critical to improving our currently incomplete understanding of PCC's complex pathophysiology. This review provides an overview of the main clinical phenotypes of PCC, characterises these phenotypes by examining symptoms and signs, as well as the associated risk factors. The main hypothesised pathophysiological mechanisms are discussed by outlining the current knowledge on PCC pathology, focussing on the most commonly affected organ systems. Current PCC management includes supportive care such as physiotherapy and the repurposing of existing drugs primarily targeting persistence of SARS-CoV-2 (e.g. antivirals, monoclonal antibodies) and immune dysfunction (e.g. antiinflammatory drugs, immunomodulators). To date, prevention of SARS-CoV-2 infection remains critical, which can be achieved through effective public health measures and vaccination strategies. Finally, this review highlights current knowledge gaps and proposes future research directions to advance the understanding and treatment of PCC. © 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 4-5","pages":"369-389"},"PeriodicalIF":5.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6443","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256929","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}
引用次数: 0
Resistance mechanisms and clonal dynamics in mantle cell lymphoma treated with sequential BTKi and venetoclax therapy 连续BTKi和venetoclax治疗套细胞淋巴瘤的耐药机制和克隆动力学。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-05-15 DOI: 10.1002/path.6434
Tamás László, László Imre Pinczés, Bence Bátai, Luca Varga, Botond Timár, Anita Gulyás, Ilona Tárkányi, Márk Plander, Zsolt Nagy, Péter Rajnics, Miklós Egyed, Zsuzsa Molnár, János Rottek, András Masszi, Péter Tamáska, Róbert Szász, Árpád Illés, Donát Alpár, Ferenc Magyari, Csaba Bödör
{"title":"Resistance mechanisms and clonal dynamics in mantle cell lymphoma treated with sequential BTKi and venetoclax therapy","authors":"Tamás László,&nbsp;László Imre Pinczés,&nbsp;Bence Bátai,&nbsp;Luca Varga,&nbsp;Botond Timár,&nbsp;Anita Gulyás,&nbsp;Ilona Tárkányi,&nbsp;Márk Plander,&nbsp;Zsolt Nagy,&nbsp;Péter Rajnics,&nbsp;Miklós Egyed,&nbsp;Zsuzsa Molnár,&nbsp;János Rottek,&nbsp;András Masszi,&nbsp;Péter Tamáska,&nbsp;Róbert Szász,&nbsp;Árpád Illés,&nbsp;Donát Alpár,&nbsp;Ferenc Magyari,&nbsp;Csaba Bödör","doi":"10.1002/path.6434","DOIUrl":"10.1002/path.6434","url":null,"abstract":"<p>In recent years, targeted therapies have become the standard of care for refractory/relapsed mantle cell lymphoma (MCL). Although the mutational profile of MCL has been extensively studied, there is a lack of understanding of resistance mechanisms and genetic factors that impact the response to novel treatments. Since patients relapsing on targeted treatment experience poor clinical outcomes, understanding the genetic foundation of resistance mechanisms in MCL is essential. In this study, we aimed to scrutinize the copy number profile and clonal dynamics of double-resistant MCL patients treated sequentially with Bruton's tyrosine kinase inhibitor (BTKi) and venetoclax using low-coverage whole genome sequencing (lcWGS). Samples obtained after systemic therapy showed more copy number alterations (CNAs) (<i>p</i> = 0.039; Wilcoxon) compared to samples collected before treatment initiation. Patients showing early progression on BTKi demonstrated CNAs affecting cytobands encompassing the coding regions of <i>NOTCH1</i>, <i>TRAF2</i>, <i>BIRC2</i>, <i>BIRC3</i>, and <i>ATM</i>. A deletion in chromosome 9p21.3 was identified in two out of three venetoclax-resistant patients. For patient MCL2, progressing on ibrutinib but showing venetoclax resistance, a 9p21.3 deletion was found throughout the disease course, with acquired <i>SMARCA4</i>-del(19)(p13.3–q13.11) and <i>DLC1</i>–del(8)(p23.2–q11.1) observed at relapse, highlighting their role in disease progression and therapy resistance. Using lcWGS, an innovative genome-wide approach, this study revealed novel putative primary and acquired resistance mechanisms in BTKi and venetoclax double-resistant MCL patients. © 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 4-5","pages":"395-404"},"PeriodicalIF":5.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6434","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075079","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}
引用次数: 0
NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration NSD1突变状态通过调节线粒体呼吸决定头颈部鳞状细胞癌代谢抑制剂的敏感性。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-05-15 DOI: 10.1002/path.6430
Shouyi Tang, Qing Wang, Zhen Wang, Luyao Cai, Dan Pan, Jing Li, Qianming Chen, Yu Zhou, Ying-Qiang Shen
{"title":"NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration","authors":"Shouyi Tang,&nbsp;Qing Wang,&nbsp;Zhen Wang,&nbsp;Luyao Cai,&nbsp;Dan Pan,&nbsp;Jing Li,&nbsp;Qianming Chen,&nbsp;Yu Zhou,&nbsp;Ying-Qiang Shen","doi":"10.1002/path.6430","DOIUrl":"10.1002/path.6430","url":null,"abstract":"<p>Head and neck squamous cell carcinomas (HNSCCs) are the most common malignant tumors in the head and neck region, characterized by a high recurrence rate and early metastasis. Despite advances in treatment, patient outcomes and prognosis remain poor, highlighting the urgent need for new therapeutic strategies. Recent research has increasingly focused on targeting glucose metabolism as a therapeutic strategy for cancer, revealing multiple promising targets and potential drugs. However, the metabolic heterogeneity among tumors leads to variable sensitivity to metabolic inhibitors in different patients, limiting their clinical utility. In this study, we employed bioinformatics analysis, cell experiments, animal models, and multi-omics approaches to reveal differences in glucose metabolism phenotypes among HNSCC patients and elucidated the underlying molecular mechanisms driving these differences. Our findings showed that <i>NSD1</i> mutation status affects the glucose metabolism phenotype in HNSCC, with <i>NSD1</i> wild-type HNSCC exhibiting higher mitochondrial respiration and <i>NSD1</i> mutant HNSCC showing weaker mitochondrial respiration but enhanced glycolysis. We further demonstrated that <i>NSD1</i> regulates mitochondrial respiration in HNSCC via epigenetic modulation of the <i>TGFB2</i>/<i>PPARGC1A</i> signaling axis. Additionally, we found that <i>NSD1</i> wild-type HNSCC is more sensitive to mitochondrial respiration inhibitors, whereas <i>NSD1</i> mutant HNSCC shows increased sensitivity to glycolysis inhibitors. In summary, we found that <i>NSD1</i> can epigenetically regulate the <i>TGFB2</i>/<i>PPARGC1A</i> axis to modulate mitochondrial respiration and sensitivity to metabolic inhibitors in HNSCC. These findings suggest a novel strategy for selecting metabolic inhibitors for HNSCC based on the <i>NSD1</i> gene status of patients. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":"306-321"},"PeriodicalIF":5.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075077","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}
引用次数: 0
Mucinous cystic neoplasms and simple mucinous cysts are two distinct precursors of pancreatic cancer: clinicopathological, genomic, and transcriptomic characterization 粘液囊性肿瘤和单纯性粘液囊肿是胰腺癌的两种不同的前体:临床病理学、基因组学和转录组学特征。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-05-15 DOI: 10.1002/path.6437
Antonio Pea, Michele Bevere, Anastasios Gkountakos, Davide Pasini, Denise Fiorini, Andrea Mafficini, Stela Golovco, Michele Simbolo, Serena Pedron, Concetta Sciammarella, Paola Mattiolo, Aldo Mombello, Manuela Villanova, Carlotta Franzina, Francesca Masetto, Calogero Ciulla, Nicola Sperandio, Kohei Fujikura, Masha S. Ahadi, Jaswinder S. Samra, Amber L. Johns, Joanne Verheij, Martijn W.J. Stommel, Hjalmar van Santvoort, Leonor Schubert Santana, Giuseppe Malleo, Michele Milella, Lodewijk A. A. Brosens, Laura D. Wood, David K. Chang, Riccardo De Robertis, Mirko D'Onofrio, Anthony J. Gill, Roberto Salvia, Vincenzo Corbo, Rita T. Lawlor, Aldo Scarpa, Claudio Luchini
{"title":"Mucinous cystic neoplasms and simple mucinous cysts are two distinct precursors of pancreatic cancer: clinicopathological, genomic, and transcriptomic characterization","authors":"Antonio Pea,&nbsp;Michele Bevere,&nbsp;Anastasios Gkountakos,&nbsp;Davide Pasini,&nbsp;Denise Fiorini,&nbsp;Andrea Mafficini,&nbsp;Stela Golovco,&nbsp;Michele Simbolo,&nbsp;Serena Pedron,&nbsp;Concetta Sciammarella,&nbsp;Paola Mattiolo,&nbsp;Aldo Mombello,&nbsp;Manuela Villanova,&nbsp;Carlotta Franzina,&nbsp;Francesca Masetto,&nbsp;Calogero Ciulla,&nbsp;Nicola Sperandio,&nbsp;Kohei Fujikura,&nbsp;Masha S. Ahadi,&nbsp;Jaswinder S. Samra,&nbsp;Amber L. Johns,&nbsp;Joanne Verheij,&nbsp;Martijn W.J. Stommel,&nbsp;Hjalmar van Santvoort,&nbsp;Leonor Schubert Santana,&nbsp;Giuseppe Malleo,&nbsp;Michele Milella,&nbsp;Lodewijk A. A. Brosens,&nbsp;Laura D. Wood,&nbsp;David K. Chang,&nbsp;Riccardo De Robertis,&nbsp;Mirko D'Onofrio,&nbsp;Anthony J. Gill,&nbsp;Roberto Salvia,&nbsp;Vincenzo Corbo,&nbsp;Rita T. Lawlor,&nbsp;Aldo Scarpa,&nbsp;Claudio Luchini","doi":"10.1002/path.6437","DOIUrl":"10.1002/path.6437","url":null,"abstract":"<p>Mucinous cystic neoplasms (MCNs) of the pancreas are macroscopic precursors of pancreatic cancer. A similar cystic lesion but lacking the ovarian-type subepithelial stroma has been recently defined as a simple mucinous cyst (SMC); however, its nature remains unclear. This study aims to define the clinicopathological and molecular profiles of a cohort of MCNs and SMCs of the pancreas and their associated invasive carcinoma. Overall, 23 cases were identified, comprising 19 MCNs and 4 SMCs with co-occurring invasive carcinoma. A multiregional (two samples from each cystic lesion and one from the adenocarcinoma) DNA and RNA sequencing approach was used. The key findings can be summarized as follows: (1) Molecular association: In 22/23 cases (95.7%), the concomitant mucinous cyst and invasive carcinoma shared specific genomic alterations, establishing for the first time that SMC is a true precursor of pancreatic cancer. (2) Clinical behavior: carcinomas arising from SMC appeared to be more aggressive than those arising from MCN. (3) Mutational profile: both cyst types showed significant similarities to conventional pancreatic ductal adenocarcinoma (PDAC), with <i>KRAS</i> and <i>TP53</i> the most commonly altered genes. (4) Intracystic heterogeneity: while most molecular alterations were present in both analyzed cystic areas, <i>RNF43</i> showed the highest heterogeneity. (5) <i>CDKN2A</i>: its alterations were predominantly restricted to the invasive component, suggesting a role in driving the invasion in a subset of cases. <i>CNKN2A</i> may also serve as a potential biomarker for identifying high-risk cysts. (6) RNAseq: most cases showed a switch from the classical to the basal transcriptome subtype during the progression from cystic neoplasms to invasive cancers. These findings establish SMCs as new precursors of pancreatic cancer and provide critical insights into the tumorigenesis of MCNs, with potential immediate implications for tumor taxonomy and clinical management. © 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 4-5","pages":"421-434"},"PeriodicalIF":5.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075070","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}
引用次数: 0
Cystathionine gamma-lyase-mediated hypoxia inducible factor 1-alpha expression drives clear cell ovarian cancer progression 半胱硫氨酸γ裂解酶介导的缺氧诱导因子1- α表达驱动透明细胞卵巢癌进展。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-05-15 DOI: 10.1002/path.6433
Amal M EL-Naggar, Yuqin Li, Busra Turgu, Yuchen Ding, Longyijie Wei, Shary Yuting Chen, Genny Trigo-Gonzalez, Forouh Kalantari, Rodrigo Vallejos, Branden Lynch, Janine Senz, Amy Lum, J Maxwell Douglas, Clara Salamanca, Shelby Thornton, Yimei Qin, Kiran Parmar, Sandra E Spencer, Samuel Leung, Michelle MM Woo, Paul J Yong, Hai-Feng Zhang, Christopher S Hughes, Gian Luca Negri, Yemin Wang, Gregg B Morin, Poul H Sorensen, David G Huntsman
{"title":"Cystathionine gamma-lyase-mediated hypoxia inducible factor 1-alpha expression drives clear cell ovarian cancer progression","authors":"Amal M EL-Naggar,&nbsp;Yuqin Li,&nbsp;Busra Turgu,&nbsp;Yuchen Ding,&nbsp;Longyijie Wei,&nbsp;Shary Yuting Chen,&nbsp;Genny Trigo-Gonzalez,&nbsp;Forouh Kalantari,&nbsp;Rodrigo Vallejos,&nbsp;Branden Lynch,&nbsp;Janine Senz,&nbsp;Amy Lum,&nbsp;J Maxwell Douglas,&nbsp;Clara Salamanca,&nbsp;Shelby Thornton,&nbsp;Yimei Qin,&nbsp;Kiran Parmar,&nbsp;Sandra E Spencer,&nbsp;Samuel Leung,&nbsp;Michelle MM Woo,&nbsp;Paul J Yong,&nbsp;Hai-Feng Zhang,&nbsp;Christopher S Hughes,&nbsp;Gian Luca Negri,&nbsp;Yemin Wang,&nbsp;Gregg B Morin,&nbsp;Poul H Sorensen,&nbsp;David G Huntsman","doi":"10.1002/path.6433","DOIUrl":"10.1002/path.6433","url":null,"abstract":"<p>Clear cell ovarian cancer (CCOC) is the second most common ovarian cancer subtype, accounting for 5%–11% of ovarian cancers in North America. Late-stage CCOC is associated with a worse prognosis compared to other ovarian cancer histotypes, a challenge that has seen limited progress in recent decades. CCOC typically originates within the toxic microenvironment of endometriotic ovarian cysts and is characterized by its intrinsic chemoresistance, a strong hypoxic signature, and abundant expression of cystathionine gamma-lyase (CTH). CTH is a key enzyme in the transsulfuration pathway and serves as a marker of ciliated cells derived from the Müllerian tract. CTH plays a pivotal role in <i>de novo</i> cysteine synthesis, which is essential for glutathione (GSH) production and redox homeostasis. Using an array of molecular tools and cancer models, including <i>in vivo</i> studies, we demonstrated that CTH expression was induced under various stress conditions, such as exposure to endometriotic cyst content and hypoxia. This induction enables cell survival and creates a differentiation state manifested by CCOC that potentiates tumor progression and metastasis. In addition to regulating redox homeostasis, CTH enhances hypoxia inducible factor 1-alpha (HIF1α) expression, independently of hydrogen sulfide (H<sub>2</sub>S) production. Re-expression of HIF1α in <i>CTH</i> KO cells fully restored metastatic capacity in <i>in vivo</i> models. Co-expression of CTH and HIF1α proteins was also observed in human CCOC samples. Importantly, targeting CTH in CCOC significantly reduced its metastatic potential in <i>in vivo</i> models and enhanced sensitivity to chemotherapy. These findings underscore that CTH is both a defining feature of CCOC and a promising therapeutic target, not only for CCOC patients but also for those with other CTH-expressing cancers. © 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 3","pages":"352-367"},"PeriodicalIF":5.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6433","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075065","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}
引用次数: 0
The TBXT rs2305089 SNP links the benign notochordal cell tumour and chordoma TBXT rs2305089 SNP将良性脊索细胞瘤和脊索瘤联系起来。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-05-05 DOI: 10.1002/path.6427
Inga Usher, Paul O'Donnell, Lorena Ligammari, Dorothee Harder, Wendy Brown, David Choi, Paul Cool, Lucia Cottone, Adrienne M Flanagan
{"title":"The TBXT rs2305089 SNP links the benign notochordal cell tumour and chordoma","authors":"Inga Usher,&nbsp;Paul O'Donnell,&nbsp;Lorena Ligammari,&nbsp;Dorothee Harder,&nbsp;Wendy Brown,&nbsp;David Choi,&nbsp;Paul Cool,&nbsp;Lucia Cottone,&nbsp;Adrienne M Flanagan","doi":"10.1002/path.6427","DOIUrl":"10.1002/path.6427","url":null,"abstract":"<p>The aim of this research was to investigate the pathogenesis of the bone cancer chordoma and the role of the germline rs2305089 SNP in <i>TBXT</i>. Using medical imaging and genotyping studies, we observed that benign notochordal cell tumours (BNCTs) were associated with chordomas and with the variant rs2305089 A-allele with enrichment of the AA genotype compared to controls. We engineered <i>in vitro</i> mesoderm models, representing notochord, which showed higher expression of <i>TBXT</i> and activation of its regulatory network in the presence of the variant A allele. Heterozygotes (GA) displayed enrichment of Wnt/β-catenin and epithelial mesenchymal transition pathways, faster cell migratory capacity, and altered expression of endoplasmic reticulum and intracellular transport mediators. WT lines (GG) were enriched for metabolic pathways and MTORC1 signalling, suggesting that rs2305089 genotype regulates notochord vacuoles during notochord regression. By leveraging patient-derived data and functional studies, we show that the variant rs2305089 A-allele predisposes to BNCTs and ultimately to chordomas. © 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 3","pages":"247-257"},"PeriodicalIF":5.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6427","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959499","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}
引用次数: 0
Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes KRAS野生型胰腺导管腺癌的临床病理和分子特征揭示了RAS通路基因的致癌突变和融合的前驱病变。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-05-02 DOI: 10.1002/path.6432
Kazuhiro Toriyama, Katsuhiro Masago, Noriko Shibata, Masataka Haneda, Takamichi Kuwahara, Seiji Natsume, Shota Kobayashi, Yasuko Fujita, Eiichi Sasaki, Kenji Yamao, Hiroki Kawashima, Yasuhiro Shimizu, Kazuo Hara, Yasushi Yatabe, Waki Hosoda
{"title":"Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes","authors":"Kazuhiro Toriyama,&nbsp;Katsuhiro Masago,&nbsp;Noriko Shibata,&nbsp;Masataka Haneda,&nbsp;Takamichi Kuwahara,&nbsp;Seiji Natsume,&nbsp;Shota Kobayashi,&nbsp;Yasuko Fujita,&nbsp;Eiichi Sasaki,&nbsp;Kenji Yamao,&nbsp;Hiroki Kawashima,&nbsp;Yasuhiro Shimizu,&nbsp;Kazuo Hara,&nbsp;Yasushi Yatabe,&nbsp;Waki Hosoda","doi":"10.1002/path.6432","DOIUrl":"10.1002/path.6432","url":null,"abstract":"<p>Pancreatic ductal adenocarcinomas (PDACs) with wild-type <i>KRAS</i> constitute a small fraction of PDACs, and these tumors were recently shown to harbor frequent actionable oncogenic mutations and fusions. However, the clinicopathological features of <i>KRAS</i> wild-type PDAC have not been well studied. Additionally, precancerous lesions occurring in patients with <i>KRAS</i> wild-type PDACs have rarely been characterized. Here, we investigated the clinicopathological characteristics and outcomes of 75 patients with <i>KRAS</i> wild-type PDAC. Molecular analyses were performed in 40 patients using targeted DNA and whole-exome sequencing and targeted RNA sequencing. We demonstrated that patients with metastatic PDAC with wild-type <i>KRAS</i> were younger (median 59.5 years) than those with mutated <i>KRAS</i> (median 67 years, <i>p</i> &lt; 0.000055). The wild-type <i>KRAS</i> status was not a significant prognostic factor for metastatic disease. Molecularly, genes in the RAS pathway are frequently mutated or rearranged (46%, 16/35), including mutations in <i>BRAF</i>, <i>NRAS</i>, <i>HRAS</i>, <i>EGFR</i>, <i>MAP2K1</i>, <i>FGFR1</i>, <i>FGFR3</i> and <i>ERBB4</i> and fusions of <i>FGFR2</i> (<i>FGFR2</i>::<i>CCDC147</i>, <i>FGFR2</i>::<i>CAT</i>, <i>FGFR2</i>::<i>TXLNA</i>), <i>ALK</i> (<i>STRN</i>::<i>ALK</i>, <i>EML4</i>::<i>ALK</i>), and <i>BRAF</i> (<i>TRIP11</i>::<i>BRAF</i>). Mismatch repair deficiency was identified in 10% (4/39) of patients. Potentially actionable alterations were identified frequently in <i>KRAS</i> wild-type PDACs (30%, 12/40), in which nontubular-type carcinomas were significantly enriched with actionable alterations compared with tubular adenocarcinomas [67% (6/9) versus 16% (5/31); <i>p</i> = 0.007]. Finally, we investigated the precursors of PDACs in 13 pancreatectomy specimens from patients with <i>KRAS</i> wild-type PDAC. We identified three pancreatic intraepithelial neoplasias (PanINs) and two intraductal papillary mucinous neoplasms (IPMNs) harboring oncogenic fusions of <i>ALK</i> and <i>BRAF</i> and driver mutations in <i>BRAF</i> and <i>AKT1</i>. This study suggests that in the context of unmutated <i>KRAS</i>, PDAC is driven by alternative oncogenic mutations or fusions of RAS pathway genes, which may be introduced during the early phase of tumorigenesis. © 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 3","pages":"337-351"},"PeriodicalIF":5.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6432","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964593","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}
引用次数: 0
Correction to ‘Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice’ 更正“内皮素和血管紧张素受体的双重抑制改善了Alport小鼠的肾脏和内耳病变”。
IF 5.6 2区 医学
The Journal of Pathology Pub Date : 2025-05-02 DOI: 10.1002/path.6425
{"title":"Correction to ‘Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice’","authors":"","doi":"10.1002/path.6425","DOIUrl":"10.1002/path.6425","url":null,"abstract":"<p>\u0000 <span>Dominic, Cosgrove</span>, <span>Michael, Anne Gratton</span>, <span>Jacob, Madison</span>, <span>Denise, Vosik</span>, <span>Gina, Samuelson</span>, <span>Daniel, Meehan</span>, <span>Duane, Delimont</span>, <span>Grady, Phillips</span>, <span>Brendan, Smyth</span>, <span>Tiziano, Pramparo</span>, <span>Diana, Jarocki</span>, <span>Mai, Nguyen</span>, <span>Radko, Komers</span> and <span>Celia, Jenkinson</span>. <i>J Pathol</i> <span>2023</span>; <span>260</span><b>:</b> <span>353</span>–<span>364</span>. https://doi.org/10.1002/path.6087\u0000 </p><p>The corresponding author has informed the editors that in this article, first published on 31 May 2023 in Wiley Online Library (wileyonlinelibrary.com), a typographical error exists in the legend of Figure 6.</p><p>The figure is correct, but the legend for panel D should read ‘(D) Hearing loss in AS-LS mice was worse compared with WT-LS mice (*<i>p</i> &lt; 0.05 WT-LS versus AS-LS)’.</p><p>The authors apologise for any inconvenience this error may have caused.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"266 3","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6425","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954537","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}
引用次数: 0
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