The Journal of Pathology最新文献

{"title":"Alternative driver pathways in peripheral nerve sheath tumors - including DICER1 and/or KRAS alterations.","authors":"Hsin-Yi Chang, Carla Saoud, Dianne Torrence, William Tap, Ping Chi, Cristina R Antonescu","doi":"10.1002/path.6391","DOIUrl":"https://doi.org/10.1002/path.6391","url":null,"abstract":"<p><p>DICER1-associated sarcoma is an emerging entity, defined by either somatic or germline dicer 1, ribonuclease III (DICER1) mutations and sharing characteristic morphologic features irrespective of the site of origin. In addition to the DICER1 driver mutation, concurrent genomic alterations, including tumor protein 53 (TP53) inactivation and RAS pathway activation, are frequently detected. Tumors that morphologically resemble malignant peripheral nerve sheath tumor (MPNST) have rarely been reported among DICER1 sarcomas and often pose diagnostic challenges. This study was prompted by a case involving morphologic features of MPNST, which harbored co-existing DICER1 and hotspot KRAS mutations. Hence, we investigated the incidence of these alterations in PNST from our molecular database compared to the genomic and morphologic spectrum of DICER1-mutant sarcomas. In total, we identified three cases diagnosed as MPNST with co-existing DICER1, ATRX chromatin remodeler (ATRX), and KRAS G12V/A alterations occurring in brain, cerebellopontine angle, and intra-abdominal sites. Two additional cases each of MPNSTs and neurofibromas were identified with hotspot KRAS mutations. All five MPNSTs lacked canonical neurofibromin 1 (NF1)/neurofibromin 2 (NF2) alterations, displaying a classic morphologic appearance with fascicular monomorphic spindle cells and followed a diverse clinical behavior. Among the 38 DICER1-associated sarcomas in our database, eight (21%) had secondary KRAS hotspot mutations, all composed of monomorphic spindle and/or round cells, including three with an MPNST-like histology. In contrast, all 10 (26%) DICER1-mutant sarcomas with TP53 mutations showed a pleomorphic phenotype. The DNA-based methylation profile of our index case clustered within the group of sarcomas with DICER1 alterations. Our results highlight a small subset of MPNST associated with DICER1 and/or KRAS mutations. However, their relationship with conventional MPNST remains to be determined in larger studies. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021324","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":"SMARCB1-deficient malignant melanocytic uveal tumours: a new neural crest-derived tumour entity with SMARCB1-related germline predisposition.","authors":"Joanna Cyrta, Julien Masliah-Planchon, Owen Hoare, Riwan Brillet, Mamy Andrianteranagna, Pierre Sohier, Liesbeth Cardoen, Yassine Bouchoucha, Mathilde Filser, Andreia Goncalves, Martial Caly, Paul Fréneaux, Kalliopi Stefanaki, Maria Pefkianaki, Maria Moschovi, Alexandre Matet, Nathalie Cassoux, Livia Lumbroso-Le Rouic, Marion Gauthier-Villars, Marc-Henri Stern, Anne Vincent-Salomon, Manuel Rodrigues, Franck Bourdeaut","doi":"10.1002/path.6390","DOIUrl":"https://doi.org/10.1002/path.6390","url":null,"abstract":"<p><p>Rhabdoid tumours (RT) are an aggressive malignancy affecting <2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (SMARCB1) in nearly all cases. Germline SMARCB1 alterations are found in ~30% of patients and define the RT Predisposition Syndrome type 1 (RTPS1). Uveal melanoma (UVM), the most common primary intraocular cancer in adults, does not harbour SMARCB1 alterations. We report two cases of a previously undescribed intraocular malignancy that shared some features with UVM and RT, but was also distinct from these entities. Both female patients, aged 23 and 14 years, underwent enucleation, and the tumours were subjected to comprehensive genomic, DNA methylation, and transcriptomic profiling. Pathological examination showed large, amelanotic intraocular tumours with epithelioid features, expressing melanocytic markers [S100P, SOX10, Melan-A, PMEL (HMB45), TYR] as seen using immunohistochemistry (IHC), but with little or no melanin production. Both tumours harboured biallelic loss-of-function SMARCB1 alterations, associated with loss of SMARCB1 (BAF47/INI1) expression on IHC. Their genomic profiles were atypical both for UVM and for RT, and no pathogenic variants were found in other genes tested, including those recurrently altered in UVM. In both patients, a germline SMARCB1 variant was found. However, there was no relevant family history of cancer. Transcriptome and methylome profiling suggested that these tumours were distinct from RT, UVM, and skin melanomas. RNAseq confirmed expression of early and late genes related to melanocytic differentiation. The first patient died of metastatic disease 16 months after diagnosis, the second was disease-free 10 months after completion of treatment. In summary, we report two cases of a previously undescribed, aggressive SMARCB1-deficient intraocular malignancy with melanocytic differentiation, which occurs in young patients, is distinct from UVM and RT, and expands the RTPS1 spectrum. © 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":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031835","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":"C1GALT1 expression predicts poor survival in osteosarcoma and is crucial for ABCC1 transporter-mediated doxorubicin resistance.","authors":"Chun-Wei Liu, Jing-Hui Huang, Hsiu-Hao Chang, Chia-Hua Chen, Yi-Huan Tsai, Wei-Li Chen, Jung-An Lin, Hsiu-Ling Chang, Cheng-Chang Chen, Mei-Chun Lin, Min-Chuan Huang, Neng-Yu Lin","doi":"10.1002/path.6384","DOIUrl":"https://doi.org/10.1002/path.6384","url":null,"abstract":"<p><p>Osteosarcoma is an aggressive bone malignancy with a high propensity for drug resistance and metastasis, leading to poor clinical outcomes. This study investigates the role of core 1 β1,3-galactosyltransferase 1 (C1GALT1) in osteosarcoma, focusing on its implications in chemoresistance. Our findings reveal that high expression of C1GALT1 is associated with advanced stages, adverse overall survival, and increased recurrence rates. Elevated levels of C1GALT1 were observed in doxorubicin-selected osteosarcoma cells, where its suppression significantly promoted doxorubicin-induced apoptosis and reduced drug efflux. Pharmacological inhibition of C1GALT1 using itraconazole replicated these effects, suggesting a potential therapeutic strategy to overcome chemoresistance. Additionally, we identified the involvement of the ATP-binding cassette (ABC) transporter ABCC1 in the drug-resistance phenotype mediated by C1GALT1. C1GALT1-mediated O-glycan changes were found to influence the cell-surface targeting and lysosomal degradation of ABCC1, thereby modulating its efflux capacity. In vitro and in vivo studies confirmed that C1GALT1 impacts ABCC1 expression and function, further supporting its role in osteosarcoma chemoresistance. These results highlight the clinical relevance of C1GALT1 as a biomarker for prognosis and a potential therapeutic target for osteosarcoma. © 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":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021414","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":"CHIT1 regulates the neuroinflammation and phagocytosis of microglia and suppresses Aβ plaque deposition in Alzheimer's disease.","authors":"Shiyun Yuan, Fuxin Zhong, Tianchi Wan, Zhangjin Qin, Lihua Chen, Dianxia Xing, Wenbo Zhang, Wuhan Yu, Lihong Huang, Jiaqi Song, Weihua Yu, Yang Lü","doi":"10.1002/path.6387","DOIUrl":"https://doi.org/10.1002/path.6387","url":null,"abstract":"<p><p>Chitinase 1 (CHIT1), as a chitin-specific hydrolase, significantly influences the progression of Alzheimer's disease (AD) through microglia-associated inflammation and amyloid beta (Aβ) plaque accumulation. However, the precise mechanism of CHIT1 action in AD remains uncertain. The effects of CHIT1 on cerebral blood flow (CBF), hippocampal volume, and cognitive function were investigated in APP/PS1 mice. Protein alterations resulting from CHIT1 overexpression were analyzed using four-dimensional (4D) label-free quantitative (LFQ) protein spectrometry. Additionally, the influence of CHIT1 on microglial electrophysiology was assessed using patch clamp measurements, and its effects on neuroinflammation, phagocytosis, microglia migration, and neuronal apoptosis under AD-like conditions were examined using the cell lines N9, BV-2, and HT-22. CHIT1 ameliorated hippocampal atrophy, hypoperfusion, and cognitive function deficits in the APP/PS1 mouse. CHIT1 regulates microglial function and neuronal protection through its interactions in AD. Increased levels of CHIT1/IDH1 contributed to an anti-inflammatory phenotype in microglia via the Ca2⁺-activated K+ channel, enhanced microglial phagocytosis, and promoted Aβ clearance. Conversely, knocking down IDH1 reduced the secretion of anti-inflammatory agents and increased the production of inflammatory factors, as well as diminishing the expression of phagocytic factors and inhibiting Aβ endocytosis. Moreover, CHIT1 reduced neuronal apoptosis by diminishing the expression of apoptotic factors. However, IDH1 knockdown abrogated the protective effect of CHIT1 on neurons. CHIT1 exerts a protective role in AD pathogenesis through its interaction with IDH1. The CHIT1/IDH1 pathway promotes Aβ clearance via a shift in microglia toward an anti-inflammatory state and prevents neuronal apoptosis and dysfunction caused by Aβ toxicity. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997165","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":"Oronasal mucosal melanoma is defined by two transcriptional subtypes in humans and dogs with implications for diagnosis and therapy.","authors":"Kelly L Bowlt Blacklock, Kevin Donnelly, Yuting Lu, Jorge Del Pozo, Laura Glendinning, Gerry Polton, Laura Selmic, Jean-Benoit Tanis, David Killick, Maciej Parys, Joanna S Morris, Inge Breathnach, Stefano Zago, Sara M Gould, Darren J Shaw, Michael S Tivers, Davide Malucelli, Ana Marques, Katarzyna Purzycka, Matteo Cantatore, Marie E Mathers, Mark Stares, Alison Meynert, E Elizabeth Patton","doi":"10.1002/path.6377","DOIUrl":"https://doi.org/10.1002/path.6377","url":null,"abstract":"<p><p>Mucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for preclinical trials. Comprehensive data on this tumour type are scarce, and existing data often overlooks the importance of the anatomical site of origin. We evaluated human and canine oronasal mucosal melanoma (OMM) to determine whether the common canine disease could inform the rare human equivalent. Using a human and canine primary OMM cohort of treatment-naive archival tissue, alongside clinicopathological data, we obtained transcriptomic, immunohistochemical, and microbiome data from both species. We defined the transcriptomic landscape in both species and linked our findings to immunohistochemical, microbiome, and clinical data. Human and dog OMM stratified into two distinctive transcriptional groups, which we defined using a species-independent 41-gene signature. These two subgroups are termed CTLA4-high and MET-high and indicate actionable targets for OMM patients. To guide clinical decision-making, we developed immunohistochemical diagnostic tools that distinguish between transcriptomic subgroups. We found that OMM had conserved transcriptomic subtypes and biological similarity between human and canine OMM, with significant implications for patient classification, treatment, and clinical trial design. © 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":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997166","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":"Recombinant Klotho administration after myocardial infarction reduces ischaemic injury and arrhythmias by blocking intracellular calcium mishandling and CaMKII activation.","authors":"Sara Vázquez-Sánchez, Ana Blasco, Pablo Fernández-Corredoira, Paula Cantolla, Elisa Mercado-García, Elena Rodríguez-Sánchez, Laura González-Lafuente, Jonay Poveda, Daniel González-Moreno, Andrea Matutano, Sonia Peribañez, Inés García-Consuegra, Massimo Volpe, María Fernández-Velasco, Luis M Ruilope, Gema Ruiz-Hurtado","doi":"10.1002/path.6388","DOIUrl":"https://doi.org/10.1002/path.6388","url":null,"abstract":"<p><p>Ischaemic heart disease (IHD) remains a major cause of death and morbidity. Klotho is a well-known anti-ageing factor with relevant cardioprotective actions, at least when renal dysfunction is present, but its actions are much less known when renal function is preserved. This study investigated Klotho as a biomarker and potential novel treatment of IHD-associated complications after myocardial infarction (MI) under preserved renal function. Association between circulating Klotho levels and cardiac injury was investigated in patients after ST-elevation MI (STEMI). Biochemical, in vivo and in vitro cardiac function and histological and molecular studies were performed to determine the effect of recombinant Klotho in the failing hearts of mice after MI. We demonstrated that STEMI patients showed lower systemic Klotho levels, with the lowest Klotho tertile in those patients with higher N-terminal pro B-type natriuretic peptide (NT-proBNP) levels. Mice also showed a decrease in systemic Klotho levels after MI induction. Furthermore, recombinant Klotho administration in mice reduced infarct area and attenuated cardiac hypertrophy and fibrosis. We also demonstrated that Klotho treatment prevented reduction in ejection fraction and MI-related ECG changes, including prolonged QRS, JT, QTc, and T_peakT_end intervals and premature ventricular contractions. In adult mouse cardiomyocytes, Klotho treatment restricted systolic calcium (Ca²⁺) release and cell shortening disturbances after MI. Klotho prevented increased diastolic Ca²⁺ leak and pro-arrhythmogenic events in PMI mice by blocking activation of the Ca²⁺/calmodulin-dependent kinase type II (CaMKII) pathway, preventing ryanodine receptor type 2 (RyR₂) hyperphosphorylation. In conclusion, Klotho supplementation protected against functional and structural cardiac remodelling and ameliorated ventricular arrhythmic events by preventing intracardiomyocyte Ca²⁺ mishandling in mice following MI. These data uncover a new cardioprotective role of Klotho, emerging as a biomarker of ventricular injury and potential treatment for patients after MI. © 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":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997167","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":"DNA methylation patterns are influenced by Pax3::Foxo1 expression and developmental lineage in rhabdomyosarcoma tumours forming in genetically engineered mouse models.","authors":"Wenyue Sun, Stephen M Hewitt, Hollis Wright, Charles Keller, Frederic G Barr","doi":"10.1002/path.6386","DOIUrl":"https://doi.org/10.1002/path.6386","url":null,"abstract":"<p><p>Rhabdomyosarcoma (RMS) is a family of phenotypically myogenic paediatric cancers consisting of two major subtypes: fusion-positive (FP) RMS, most commonly involving the PAX3::FOXO1 fusion gene, formed by the fusion of paired box 3 (PAX3) and forkhead box O1 (FOXO1) genes, and fusion-negative (FN) RMS, lacking these gene fusions. In humans, DNA methylation patterns distinguish these two subtypes as well as mutation-associated subsets within these subtypes. To investigate the biological factors responsible for these methylation differences, we profiled DNA methylation in RMS tumours derived from genetically engineered mouse models (GEMMs) in which various driver mutations were introduced into different myogenic lineages. Our unsupervised analyses of DNA methylation patterns in these GEMM tumours yielded two major clusters, corresponding to high and no/low expression of Pax3::Foxo1, which mirrored the results for human FP and FN RMS tumours. Two distinct methylation-defined subsets were found for GEMM RMS tumours with no/low Pax3::Foxo1 expression: one subset enriched in Pax7 lineage tumours and a second subset enriched in myogenic factor 5 (Myf5) lineage tumours. Integrative analysis of DNA methylation and transcriptomic data in mouse and human RMS revealed a common group of differentially methylated and differentially expressed genes, highlighting a conserved set of genes functioning in both human RMS models and GEMMs of RMS. In conclusion, these studies provide insight into the roles of oncogenic fusion proteins and developmental lineages in establishing DNA methylation patterns in FP and FN RMS respectively. © 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. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982131","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":"Silencing GRHL3 promotes multiple organ distant metastasis of lung squamous cell carcinoma cells by enhancing SOX2 stability via SIRT1.","authors":"Zhanzhan Li, Baishuang Yang, Meihua Long, Jiarong Chen, Yaofeng Zhi, Ronggang Li, Lixue Cao, Shasha Yang, Jingyi Sun, Zijie Meng, Wanting Wu, Yanyang Mai, Xin Zhang, Yanming Huang, Qiong Chen, Aibin Liu","doi":"10.1002/path.6385","DOIUrl":"https://doi.org/10.1002/path.6385","url":null,"abstract":"<p><p>Aberrant expression of grainyhead-like transcription factor 3 (GRHL3) has been extensively reported in the development and progression of several squamous cell carcinomas, such as cutaneous, head and neck, and esophageal squamous cell carcinoma. However, the clinical significance and biological roles of GRHL3 in lung squamous cell (LUSC) carcinoma are largely unclear. Herein, we report that GRHL3 was significantly upregulated in lung squamous epithelium of LUSC tissues, bronchiole, and bronchus. Moreover, expression levels of GRHL3 were decreased with the advance of pathological grade, and low GRHL3 level presented poor overall survival and short progression-free and distant metastasis-free survival in LUSC patients but had no prognostic significance in LUAD patients. Functional experiments in vivo showed that downregulating GRHL3 promoted not only lung colonization and growth but also multiple organ distant metastasis of LUSC cells, including bone, brain, and liver. Moreover, silencing GRHL3 promoted anoikis resistance and cancer stem cell (CSCs) characteristics of LUSC cells in vitro. Mechanistically, silencing GRHL3 stabilized SOX2 via SIRT1-mediated decreasing acetylation and subsequent ubiquitination-dependent degradation in LUSC cells. Thus, in-depth understanding of the underlying mechanism of GRHL3 in the progression of LUSC will facilitate the development of prognostic biomarker and therapeutic avenues against LUSC, which will present favorable prospects in improving outcomes of LUSC patients. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968885","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":"Dynamic change of polarity in spread through air spaces of pulmonary malignancies.","authors":"Yoshiaki Matsuura, Kunishige Onuma, Roberto Coppo, Hiroyuki Uematsu, Jumpei Kondo, Aya Miyagawa-Hayashino, Naoko Takeda-Miyata, Kenji Kameyama, Tatsuo Furuya, Satoru Okada, Masanori Shimomura, Masayoshi Inoue, Masahiro Inoue","doi":"10.1002/path.6382","DOIUrl":"https://doi.org/10.1002/path.6382","url":null,"abstract":"<p><p>Spread through air spaces (STAS) is a histological finding of lung tumours where tumour cells exist within the air space of the lung parenchyma beyond the margin of the main tumour. Although STAS is an important prognostic factor, the pathobiology of STAS remains unclear. Here, we investigated the mechanism of STAS by analysing the relationship between STAS and polarity switching in vivo and in vitro. Histopathological analysis revealed that apical membranes were observed outside the STAS lesions around colorectal cancer (CRC) lung metastases and lung adenocarcinomas. When apical-out CRC organoids were administered intratracheally to mice, the organoids had greater metastatic potential than did single cells. To investigate the pathobiology of STAS, we established an in vitro model of STAS in which CRC or lung cancer organoids were co-cultured with 2D-cultured mouse airway epithelial organoids (2D-MAOs). Adhesion of cancer organoids to 2D-MAOs was much less than to type I collagen or endothelial cells, suggesting a protective role of the airway epithelium against adhesion. Loss of the apical membrane of CRC organoids at the contact surface with 2D-MAOs after adhesion was responsible for establishing adhesion. When airway epithelium was stimulated by transforming growth factor beta 1 (TGF-β1), adhesion of CRC organoids was enhanced. Among TGF-β1-induced genes in airway epithelium, follistatin-like protein 1 (FSTL1) increased CRC organoid adhesion by promoting loss of the apical membrane. These results suggested that TGF-β1-induced FSTL1 may promote metastatic progression of STAS by altering the polarity status. Elucidating the mechanism of STAS could contribute to the improvement of survival in patients with pulmonary malignancies associated with STAS. © 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":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968884","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":"Podocyte YAP ablation decreases podocyte adhesion and exacerbates FSGS progression through α3β1 integrin","authors":"Guangze Shao,&nbsp;Jitu Xu,&nbsp;Chencheng Hu,&nbsp;Wenyao Jia,&nbsp;Xitong Xu,&nbsp;Yue Gu,&nbsp;Luming Zhang,&nbsp;Zhihuang Zheng,&nbsp;Jiayan Zhong,&nbsp;Siqi Zhu,&nbsp;Shenghao Meng,&nbsp;Zhonghua Zhao,&nbsp;Zhigang Zhang,&nbsp;Jun Liu,&nbsp;Yanyong Xu,&nbsp;Huijuan Wu","doi":"10.1002/path.6370","DOIUrl":"10.1002/path.6370","url":null,"abstract":"<p>Severe proteinuria in focal segmental glomerulosclerosis (FSGS) is closely associated with decreased adhesion, and subsequent loss, of podocytes. Yes-associated protein (YAP) is a key transcriptional coactivator that plays a significant role in maintaining cellular homeostasis. However, its role in podocyte adhesion and its specific mechanism in FSGS progression remain unclear. In this study, an adriamycin (ADR)-induced FSGS model was established using podocyte-specific <i>Yap</i> knockout (KO) mice and control mice. These mice were further treated with Pyrintegrin, an agonist of α3β1 integrin, or a vehicle. Additionally, an ADR-induced FSGS model was constructed using podocyte-specific <i>Itga3</i> KO mice, which were subsequently treated with 1-oleoyl lysophosphatidic acid (LPA), a YAP activator, or a vehicle. Our findings demonstrated that YAP was positively correlated with podocyte adhesion. Podocyte-specific <i>Yap</i> KO mice exhibited reduced levels of α3β1 integrin and podocyte adhesion. <i>Yap</i> KO aggravated the ADR-induced reduction in α3β1 integrin and podocyte adhesion, resulting in significantly increased segmental or global glomerulosclerosis and proteinuria. Notably, treatment with a β1 integrin agonist partially ameliorated the decrease of podocyte adhesion and the worsening FSGS progression caused by <i>Yap</i> KO. Mechanistically, YAP was found to transcriptionally regulate α3- and β1 integrin via transcriptional enhanced associate domain 3 (TEAD3), with TEAD3 binding to the promoter region of <i>Itga3</i>. Furthermore, <i>Itga3</i> KO or knockdown abolished the beneficial effects of YAP activation on podocyte adhesion and FSGS progression. In conclusion, our results demonstrate that YAP regulates podocyte adhesion and FSGS progression through its transcriptional regulation of α3β1 integrin via TEAD3. This suggests that the YAP-TEAD3-α3β1 integrin axis may serve as a promising therapeutic target for FSGS. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"84-98"},"PeriodicalIF":5.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816795","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}