The Journal of Pathology最新文献

{"title":"CRISPR–Cas9 screening identifies the role of FER as a tumor suppressor","authors":"Jiaqi Wang,&nbsp;Ran Yang,&nbsp;Fengsheng Wang,&nbsp;Junlei Zhang,&nbsp;Yutong Dong,&nbsp;Jiangjun Wang,&nbsp;Meng Yu,&nbsp;Yixiao Xu,&nbsp;Lianlian Liu,&nbsp;Yuda Cheng,&nbsp;Chen Zhang,&nbsp;Yi Yang,&nbsp;Wubin Yang,&nbsp;Jiali Wang,&nbsp;Guangxing Chen,&nbsp;Yi Huang,&nbsp;Yanping Tian,&nbsp;Rui Jian,&nbsp;Bing Ni,&nbsp;Wei Wu,&nbsp;Yan Ruan","doi":"10.1002/path.6374","DOIUrl":"10.1002/path.6374","url":null,"abstract":"<p>It is important to systematically identify tumor suppressor genes (TSGs) to improve our understanding of tumorigenesis and develop strategies for early diagnosis and mitigating disease progression. In the present study, we used an <i>in vivo</i> genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) screen and identified FPS/FES-related (<i>FER</i>) as a TSG. Single-cell RNA sequencing (scRNA-seq) revealed that normal cells with low <i>FER</i> expression exhibited elevated malignant transformation potential and stemness properties. <i>FER</i> knockout promoted the tumorigenic transformation, characterized by high colony-forming efficiency and suspension growth ability, acquired tumorigenicity <i>in vivo</i>, increased metabolic activity, dedifferentiation properties, and immune evasion. Moreover, analysis revealed that low <i>FER</i> expression tumors share molecular phenotypes with <i>FER</i> knockout cells, suggesting the consistent role of <i>FER</i> in tumor initiation and progression. Taken together, our findings not only provide insights into the essential role of <i>FER</i> as a tumor suppressor in tumor initiation and progression but also highlight its potential as a target for future clinical diagnosis. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 2","pages":"158-171"},"PeriodicalIF":5.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794100","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":"Human colonic organoids for understanding early events of familial adenomatous polyposis pathogenesis","authors":"Nolwenn Laborde,&nbsp;Alexandre Barusseaud,&nbsp;Muriel Quaranta,&nbsp;Corinne Rolland,&nbsp;Amélie Arrouy,&nbsp;Delphine Bonnet,&nbsp;Sylvain Kirzin,&nbsp;Nuria Sola-Tapias,&nbsp;Dimitri Hamel,&nbsp;Karl Barange,&nbsp;Jean-Pierre Duffas,&nbsp;Marie-Pierre Gratacap,&nbsp;Julie Guillermet-Guibert,&nbsp;Anne Breton,&nbsp;Nathalie Vergnolle,&nbsp;Laurent Alric,&nbsp;Audrey Ferrand,&nbsp;Frédérick Barreau,&nbsp;Claire Racaud-Sultan,&nbsp;Emmanuel Mas","doi":"10.1002/path.6366","DOIUrl":"10.1002/path.6366","url":null,"abstract":"<p>Patients with familial adenomatous polyposis (FAP) harbor mutations in the <i>APC</i> gene and will develop adenoma and early colorectal cancer. There is no validated treatment, and animal models are not sufficient to study FAP. Our aim was to investigate the early events associated with FAP using the intestinal organoid model in a single-center study using biopsies from nonadenomatous and adenomatous colonic mucosa of FAP patients and from healthy controls (HCs). We analyzed intestinal stem cell (ISC) activity and regulation through organoid development and expression of mRNA and proteins, as well as within colonic crypts. We used several compounds to regulate the signaling pathways controlling ISCs, such as WNT, EGFR, PI3K-AKT, TGF-β, yes-associated protein (YAP), and protease-activated receptors. In addition to their high proliferative capacity, nonadenomatous and adenomatous organoids were characterized by cysts and cysts with buds, respectively, suggesting abnormal maturation. Adenomatous organoids were enriched in the stem cell marker LGR5 and dependent on EGF and TGF-β for their growth. Downstream of EGFR, AKT, β-catenin, and YAP were found to be activated in the adenomatous organoids. While the p110β isoform of PI3K was predominant in adenomatous organoids and essential for their growth, p110α was associated with the immature state of nonadenomatous organoids. We conclude that organoids offer a relevant model for studying FAP, and this work highlights abnormal behaviors of immature cells in both nonadenomatous and adenomatous mucosa of FAP patients, which could be targeted therapeutically. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"26-40"},"PeriodicalIF":5.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783596","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":"Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells","authors":"Jaeeun Lee,&nbsp;Hayoung Woo,&nbsp;Hyunju Kang,&nbsp;Young-Ki Park,&nbsp;Ji-Young Lee","doi":"10.1002/path.6372","DOIUrl":"10.1002/path.6372","url":null,"abstract":"<p>The pathogenesis of alcohol-related liver disease (ALD) is closely linked to mitochondrial dysfunction and impaired cellular energy metabolism. In this study, we explored how ethanol triggers inflammation, oxidative stress, and mitochondrial dysfunction in Kupffer cells, i.e.hepatic resident macrophages, primarily focusing on the mitochondrial unfolded protein response (UPR^mt) using immortalized mouse Kupffer cells (ImKCs) and mouse primary KCs. The UPR^mt is a cellular defense mechanism activated in response to the perturbation of mitochondrial proteostasis to maintain mitochondrial integrity and function by upregulating the expression of mitochondrial chaperones and proteases. We also determined whether nicotinamide riboside (NR), a NAD⁺ precursor, could mitigate ethanol-triggered cellular damage. When ImKCs were exposed to 80 m<span>m</span> ethanol for 72 h, they displayed inflammation, oxidative stress, and impaired mitochondrial function with decreased mitochondrial content and deformed mitochondrial crista structure. NR, however, counteracted the effects of ethanol. Furthermore, ethanol increased mRNA and protein levels of UPR^mt genes, such as mitochondrial chaperones and proteases, which were attenuated by NR. Notably, the ethanol-induced shift in the entry of activating transcription factor 5 (ATF5), a putative transcriptional regulator of UPR^mt, to the nucleus from the mitochondria was abolished by NR. The induction of UPR^mt genes by ethanol was significantly repressed when <i>Atf5</i> was knocked down, indicating the role of ATF5 in the induction of UPR^mt genes in ImKCs exposed to ethanol. We also confirmed the induction of UPR^mt gene expression in mouse and human livers exposed to alcohol. Our findings demonstrate the ability of NR to alleviate ethanol-induced oxidative stress, inflammation, and mitochondrial dysfunction, partly by modulating the ATF5-dependent UPR^mt pathway in ImKCs, suggesting its potential for ALD therapy. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"110-122"},"PeriodicalIF":5.6,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765124","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":"Intravenous iron treatment fuels chronic kidney disease-induced arterial media calcification in rats","authors":"Astrid Van den Branden,&nbsp;Britt Opdebeeck,&nbsp;Saar Adriaensen,&nbsp;Pieter Evenepoel,&nbsp;Tom Vanden Berghe,&nbsp;Anja Verhulst","doi":"10.1002/path.6375","DOIUrl":"10.1002/path.6375","url":null,"abstract":"<p>Arterial media calcification is a severe cardiovascular complication commonly manifesting in patients with chronic kidney disease (CKD). Patients with CKD frequently undergo intravenous iron therapy to address iron deficiency. Iron is suggested to be sequestered in vascular cells, potentially leading to oxidative (lipid) stress and cell death, which are recognized as key contributors to arterial calcification. The objective of this study was to investigate the effect of intravenous iron administration on CKD-induced arterial media calcification. Therefore, adenine-induced CKD rats were treated intravenously with iron and checked for arterial iron deposition and calcification, as well as for ferritin and lipid peroxidation markers. Additionally, arterial sections from patients with CKD who were dialysis dependent were analyzed for these parameters. This study showed that intravenous iron administration in CKD rats led to arterial iron deposition and a lipid peroxidation signature. CKD-induced arterial calcification was increased upon iron treatment and correlated with arterial iron accumulation and lipid peroxidation markers. Patients with CKD who were dialysis dependent showed arterial iron accumulation and elevated lipid peroxidation, but a direct correlation with arterial calcification was lacking. Taken together, iron treatment is suggested as a potential contributor to the calcification process, instead of being a predominant factor, thereby emphasizing the complexity of arterial calcification as a multifactorial disease. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 2","pages":"172-183"},"PeriodicalIF":5.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11717497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749690","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":"Multi-omics analysis unveils the role of inflammatory cancer-associated fibroblasts in chordoma progression","authors":"Bo-Wen Zheng,&nbsp;Wei Guo","doi":"10.1002/path.6369","DOIUrl":"10.1002/path.6369","url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs) constitute the primary cellular component of the stroma in chordomas, characterized by an abundance of mucinous stromal elements, potentially facilitating their initiation and progression; however, this inference has yet to be fully confirmed. In this study, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), bulk RNA-seq, multiplexed quantitative immunofluorescence (QIF), and <i>in vivo</i> and <i>in vitro</i> experiments were performed to determine the heterogeneity, spatial distribution, and clinical significance of CAFs in chordoma. ScRNA-seq was performed on 87,693 single cells derived from seven tumor samples and four control nucleus pulposus samples. A distinct CAF cluster distinguished by the upregulated expression of inflammatory genes and enriched functionality in activating inflammation-associated cells was identified. Pseudotime trajectory and cell communication analyses suggested that this inflammatory CAF (iCAF) subset originated from normal fibroblasts and interacted extensively with tumors and various other cell types. By integrating the scRNA-seq results with ST, the presence of iCAF in chordoma tissue was further confirmed, indicating their positioning at a distance from the tumor cells. Bulk RNA-seq data analysis from 126 patients revealed a correlation between iCAF signature scores, chordoma invasiveness, and poor prognosis. QIF validation involving an additional 116 patients found that although iCAFs were not in close proximity to tumor cells compared with other CAF subsets, their density correlated with malignant tumor phenotypes and adverse outcomes. <i>In vivo</i> and <i>in vitro</i> experiments further confirmed that iCAFs accelerate the malignant progression of chordomas. These findings could provide insights into the development of novel therapeutic strategies. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"69-83"},"PeriodicalIF":5.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749697","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":"LINE-1 hypomethylation characterizes the inflammatory response in coeliac disease associated-intestinal mucosa and small bowel adenocarcinomas","authors":"Laura Libera,&nbsp;Alessandro Vanoli,&nbsp;Nora Sahnane,&nbsp;Muhammad Adnan,&nbsp;Camilla Guerini,&nbsp;Giovanni Arpa,&nbsp;Paola Ilaria Bianchi,&nbsp;Marco Vincenzo Lenti,&nbsp;Gino Roberto Corazza,&nbsp;Stefano La Rosa,&nbsp;Antonio Di Sabatino,&nbsp;Daniela Furlan","doi":"10.1002/path.6371","DOIUrl":"10.1002/path.6371","url":null,"abstract":"<p>Long interspersed nuclear elements 1 (LINE-1) are the most abundant and the only autonomous mobile elements in the human genome. When their epigenetic repression is removed, it can lead to disease, such as autoimmune diseases and cancer. Coeliac disease (CeD) is an immune-mediated disease triggered by an abnormal T-cell response to dietary gluten and a predisposing condition of small bowel adenocarcinoma (SBA), frequently characterized by epigenetic alterations. The aim of this work was to assess LINE-1 methylation by bisulphite pyrosequencing and NanoString® gene transcription analysis in 38 CeD-SBAs compared with 25 SBAs associated with Crohn's disease (CrD-SBAs) and 25 sporadic SBAs (S-SBA). Both analyses were also performed in duodenal mucosae from 12 untreated CeD patients (UCD) and 19 treated CeD patients (TCD), and in 11 samples of normal intestinal mucosa to better investigate the role of LINE-1 deregulation in CeD and in CeD-SBA. A significant loss of LINE-1 methylation was observed in CeD-SBAs and in mucosae from UCD patients (with very similar methylation levels) compared with controls. By contrast, a restoration of normal LINE-1 methylation levels was found in TCD mucosae after a strict gluten-free diet. LINE-1 hypomethylation does not lead to expression of ORF1 and ORF2, with the only exception being for one CeD-SBA. The expression analysis of enzymes modulating DNA methylation and inflammatory genes confirmed that CeD-SBA shared a very similar expression profile of UCD mucosae showing a strong upregulation of genes involved in inflammation, immune response, and T-cell activity compared with TCD mucosae. For the first time, this work demonstrates that loss of DNA methylation is an intrinsic epigenetic feature of CeD, accompanying the immune response as a reversible mechanism in patients following a strict gluten-free diet, and suggests the possible role of LINE-1 hypomethylation in promoting cell adaptability during the gliadin-related inflammatory process. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"99-109"},"PeriodicalIF":5.6,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724466","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":"Proteomic analysis of non-muscle invasive and muscle invasive bladder cancer highlights distinct subgroups with metabolic, matrisomal, and immune hallmarks and emphasizes importance of the stromal compartment","authors":"Thien-Ly Julia Dinh,&nbsp;Manuel Rogg,&nbsp;Miguel Cosenza-Contreras,&nbsp;Mujia Li,&nbsp;Max Zirngibl,&nbsp;Niko Pinter,&nbsp;Konrad Kurowski,&nbsp;Frank Hause,&nbsp;Lena Pauli,&nbsp;Fiona Imberg,&nbsp;Alana Huynh,&nbsp;Marlene Schmid,&nbsp;Ievgen Glavinsky,&nbsp;Luisa Braun,&nbsp;Clara Van Wymersch,&nbsp;Luise Bergmann,&nbsp;Xenia Ungefug,&nbsp;Marion Kunz,&nbsp;Tilman Werner,&nbsp;Patrick Bernhard,&nbsp;Guadalupe Espadas,&nbsp;Eva Brombacher,&nbsp;Julia Schueler,&nbsp;Eduard Sabido,&nbsp;Clemens Kreutz,&nbsp;Christian Gratzke,&nbsp;Martin Werner,&nbsp;Markus Grabbert,&nbsp;Peter Bronsert,&nbsp;Christoph Schell,&nbsp;Oliver Schilling","doi":"10.1002/path.6367","DOIUrl":"10.1002/path.6367","url":null,"abstract":"<p>We present the proteomic profiling of 79 bladder cancers, including treatment-naïve non-muscle-invasive bladder cancer (NMIBC, <i>n</i> = 17), muscle-invasive bladder cancer (MIBC, <i>n</i> = 51), and neoadjuvant-treated MIBC (<i>n</i> = 11). Proteins were extracted from formalin-fixed, paraffin-embedded samples and analyzed using data-independent acquisition, yielding &gt;8,000 quantified proteins. MIBC, compared to NMIBC, shows an extracellular matrix (ECM) and immune response signature as well as alteration of the metabolic proteome together with concomitant depletion of proteins involved in cell–cell adhesion and lipid metabolism. Neoadjuvant treatment did not consistently impact the proteome of the residual tumor mass. NMIBC presents two proteomic subgroups that correlate with histological grade and feature signatures of cell adhesion or lipid/DNA metabolism. Treatment-naïve MIBC presents three proteomic subgroups with resemblance to the basal-squamous, stroma-rich, or luminal subtypes and signatures of metabolism, immune functionality, or ECM. The metabolic subgroup presents an immune-depleted microenvironment, whereas the ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells. Markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T cells are a hallmark of the immune subgroup. Endogenous proteolysis is increased in MIBC alongside upregulation of matrix metalloproteases, including MMP-14. Genomic panel sequencing yielded the prototypical profile of prevalent <i>FGRF3</i> alterations in NMIBC and <i>TP53</i> alterations in MIBC. Tumor–stroma interactions of MIBC were investigated by proteomic analysis of patient-derived xenografts, highlighting specific tumor and stroma contributions to the matrisome and tumor-induced stromal proteome phenotypes. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"41-56"},"PeriodicalIF":5.6,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dominant negative Kcnd3 F227del mutation in mice causes spinocerebellar ataxia type 22 (SCA22) by impairing ER and Golgi functioning","authors":"Hao-Chih Hung,&nbsp;Jia-Han Lin,&nbsp;Yuan-Chi Teng,&nbsp;Cheng-Heng Kao,&nbsp;Pei-Yu Wang,&nbsp;Bing-Wen Soong,&nbsp;Ting-Fen Tsai","doi":"10.1002/path.6368","DOIUrl":"10.1002/path.6368","url":null,"abstract":"<p>Spinocerebellar ataxia type 22 (SCA22) caused by <i>KCND3</i> mutations is an autosomal dominant disorder. We established a mouse model carrying the <i>Kcnd3</i> F227del mutation to study the molecular pathogenesis. Four findings were pinpointed. First, the heterozygous mice exhibited an early onset of defects in motor coordination and balance which mirror those of SCA22 patients. The degeneration and a minor loss of Purkinje cells, together with the concurrent presence of neuroinflammation, as well as the previous finding on electrophysiological changes, may all contribute to the development of the SCA22 ataxia phenotype in mice carrying the <i>Kcnd3</i> F227del mutant protein. Second, the mutant protein is retained by the endoplasmic reticulum and Golgi, leading to activation of the unfolded protein response and a severe trafficking defect that affects its membrane destination. Intriguingly, profound damage of the Golgi is the earliest manifestation. Third, analysis of the transcriptome revealed that the <i>Kcnd3</i> F227del mutation down-regulates a panel of genes involved in the functioning of synapses and neurogenesis which are tightly linked to the functioning of Purkinje cells. Finally, no ataxia phenotypes were detectable in knockout mice carrying a loss-of-function <i>Kcnd3</i> mutation. Thus, <i>Kcnd3</i> F227del is a dominant-negative mutation. This mouse model may serve as a preclinical model for exploring therapeutic strategies to treat patients. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"57-68"},"PeriodicalIF":5.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674653","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":"Macrophages producing chondroitin sulfate proteoglycan-4 induce neuro-cardiac junction impairment in Duchenne muscular dystrophy","authors":"Marika Milan,&nbsp;Fabio Maiullari,&nbsp;Maila Chirivì,&nbsp;Maria Grazia Ceraolo,&nbsp;Rebecca Zigiotto,&nbsp;Andrea Soluri,&nbsp;Silvia Maiullari,&nbsp;Elisa Landoni,&nbsp;Dario Di Silvestre,&nbsp;Francesca Brambilla,&nbsp;Pierluigi Mauri,&nbsp;Veronica De Paolis,&nbsp;Nicole Fratini,&nbsp;Maria Cristina Crosti,&nbsp;Chiara Cordiglieri,&nbsp;Chiara Parisi,&nbsp;Antonella Calogero,&nbsp;Dror Seliktar,&nbsp;Yvan Torrente,&nbsp;Chiara Lanzuolo,&nbsp;Gianpietro Dotti,&nbsp;Mirco Toccafondi,&nbsp;Mauro Bombaci,&nbsp;Elena De Falco,&nbsp;Claudia Bearzi,&nbsp;Roberto Rizzi","doi":"10.1002/path.6362","DOIUrl":"10.1002/path.6362","url":null,"abstract":"<p>Duchenne muscular dystrophy (DMD) is caused by the absence of the full form of the dystrophin protein, which is essential for maintaining the structural integrity of muscle cells, including those in the heart and respiratory system. Despite progress in understanding the molecular mechanisms associated with DMD, myocardial insufficiency persists as the primary cause of mortality, and existing therapeutic strategies remain limited. This study investigates the hypothesis that a dysregulation of the biological communication between infiltrating macrophages (MPs) and neurocardiac junctions exists in dystrophic cardiac tissue. In a mouse model of DMD (<i>mdx</i>), this phenomenon is influenced by the over-release of chondroitin sulfate proteoglycan-4 (CSPG4), a key inhibitor of nerve sprouting and a modulator of the neural function, by MPs infiltrating the cardiac tissue and associated with dilated cardiomyopathy, a hallmark of DMD. Givinostat, the histone deacetylase inhibitor under current development as a clinical treatment for DMD, is effective at both restoring a physiological microenvironment at the neuro-cardiac junction and cardiac function in <i>mdx</i> mice in addition to a reduction in cardiac fibrosis, MP-mediated inflammation, and tissue CSPG4 content. This study provides novel insight into the pathophysiology of DMD in the heart, identifying potential new biological targets. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"1-13"},"PeriodicalIF":5.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613258","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":"AMIGO2 characterizes cancer-associated fibroblasts in metastatic colon cancer and induces the release of paracrine active tumorigenic secretomes","authors":"Yongsong Yong,&nbsp;Richard Demmler,&nbsp;Bisan Abdalfatah Zohud,&nbsp;Qi Fang,&nbsp;Tong Zhang,&nbsp;Yonghua Zhou,&nbsp;Katja Petter,&nbsp;Christian Flierl,&nbsp;Tobias Gass,&nbsp;Carol I Geppert,&nbsp;Susanne Merkel,&nbsp;Vera S Schellerer,&nbsp;Elisabeth Naschberger,&nbsp;Michael Stürzl","doi":"10.1002/path.6363","DOIUrl":"10.1002/path.6363","url":null,"abstract":"<p>Secretomes of cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC) contribute to malignancy. Detailed knowledge is available on the components and functions of CAF secretomes. Little is known about the regulation of CAF secretomes. Here, we searched for receptor-like membrane-bound molecules in CAFs, which may regulate the production and release of tumor-activating secretomes. The adhesion molecule with Ig-like domain 2 (AMIGO2) was significantly upregulated in cultivated CAFs compared to normal tissue-associated fibroblasts (NAFs), and this was confirmed in patient-derived tissues. AMIGO2 expression was low or absent in healthy colon, significantly increased in fibroblasts of primary CRC, and highest in the stromal tissues of CRC-derived liver metastases. AMIGO2 expression in CAFs correlated with a higher T-category, increased lymph node metastasis, progressed tumor stages and was associated with reduced survival in different cohorts of CRC patients. Interestingly, AMIGO2 expression was induced by transforming growth factor-β and higher in female patients, who exhibit a more aggressive disease course. In functional studies, conditioned media of NAFs with experimentally induced AMIGO2 overexpression enhanced proliferation and migration of different CRC tumor cells, while siRNA-mediated inhibition of AMIGO2 in CAFs attenuated these effects. Accordingly, therapeutic inhibition of the receptor-like AMIGO2 protein in CRC CAFs could prevent tumorigenic secretomes in CRC. © 2024 The Author(s). <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"265 1","pages":"14-25"},"PeriodicalIF":5.6,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613255","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}