The Journal of Pathology最新文献

{"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}

{"title":"Runt-related transcription factor 1 (RUNX1) is a mediator of acute kidney injury","authors":"Miguel Fontecha-Barriuso,&nbsp;Natalia Villar-Gomez,&nbsp;Juan Guerrero-Mauvecin,&nbsp;Julio M Martinez-Moreno,&nbsp;Susana Carrasco,&nbsp;Diego Martin-Sanchez,&nbsp;María Rodríguez-Laguna,&nbsp;Manuel J Gómez,&nbsp;María D Sanchez-Niño,&nbsp;Marta Ruiz-Ortega,&nbsp;Alberto Ortiz,&nbsp;Ana B Sanz","doi":"10.1002/path.6355","DOIUrl":"10.1002/path.6355","url":null,"abstract":"<p>Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of the pathogenesis of AKI may lead to new therapeutic approaches. Kidney transcriptomics of folic acid-induced AKI (FA-AKI) in mice identified <i>Runx1</i> as the most upregulated RUNX family gene. We then examined the expression of RUNX1 in FA-AKI, in bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI (CS-AKI), and in human AKI. In cultured mouse tubule cells, we explored the expression and role of RUNX1 in response to the cytokine TWEAK or LPS. A chemical inhibitor of RUNX1 (Ro5-3335) was used in animal models of AKI to test its potential as a therapeutic target. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubule cell nuclei. CS-AKI also upregulated kidney RUNX1. Increased tubule and interstitial RUNX1 expression were also observed in human AKI. In cultured mouse tubule cells, the pro-inflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the <i>Il6</i> gene promoter and RUNX1 targeting with the chemical inhibitor Ro5-3335, or a specific small interfering RNA (siRNA), prevented the TWEAK- and LPS-induced upregulation of IL6 through a RUNX1/NFκB1 p50 pathway. <i>In vivo</i>, preventive Ro5-3335 improved kidney function and reduced inflammation in FA-AKI and CS-AKI. However, Ro5-3335 administration after the insult only improved kidney function in CS-AKI. Kidney transcriptomics identified inflammatory genes and transcription factor mRNAs such as <i>Yap1</i> and <i>Trp53</i> as key targets of Ro5-3335 in CS-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI. © 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":"264 4","pages":"396-410"},"PeriodicalIF":5.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6355","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542410","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":"Exploring the molecular landscape of cutaneous mixed tumors characterized by TRPS1::PLAG1 gene fusion","authors":"Ziyad Alsugair,&nbsp;Marie Donzel,&nbsp;Nicolas Macagno,&nbsp;Juliet Tantot,&nbsp;Olivier Harou,&nbsp;Maxime Battistella,&nbsp;Pierre Sohier,&nbsp;Thibault Kervarrec,&nbsp;Arnaud de la Fouchardière,&nbsp;Brigitte Balme,&nbsp;Anne Champagnac,&nbsp;Marie-Delphine Lanic,&nbsp;Jonathan Lopez,&nbsp;Marick Laé,&nbsp;Françoise Descotes,&nbsp;Franck Tirode,&nbsp;Daniel Pissaloux,&nbsp;Brice Thamphya,&nbsp;Valérie Costes-Martineau,&nbsp;Nazim Benzerdjeb","doi":"10.1002/path.6359","DOIUrl":"10.1002/path.6359","url":null,"abstract":"<p>The histological similarities between pleomorphic adenomas (PAs) and cutaneous mixed tumors (CMTs) found in certain facial regions can create a diagnostic challenge. Molecular findings reveal common genetic profiles, particularly <i>PLAG1</i> rearrangements in both PA and CMT. Although molecular distinctions have received limited attention, our observations indicate multiple cases of CMTs carrying the <i>TRPS1</i>::<i>PLAG1</i> fusion. This clinical experience has driven our investigation into the potential diagnostic utility of <i>TRPS1</i>::<i>PLAG1</i> fusions for determining tumor origin. Two cohorts consisting of 46 cases of CMT and 45 cases of PA of the salivary glands were obtained from French institutions and reviewed by specialists in each subspecialty. RNA sequencing analysis was conducted to identify the molecular features of cases harboring <i>PLAG1</i>. Clinical, pathological, and molecular data were collected. In this study, cases of CMT exhibited recurrent gene fusions, primarily <i>TRPS1</i>::<i>PLAG1</i> (74%). These tumors shared characteristic histological features, including tubuloductal differentiation in 55% of cases and squamous metaplasia in varying proportions. In contrast, cases of PA had gene fusions involving <i>PLAG1</i> with various gene partners, with only one case in which <i>TRPS1</i>::<i>PLAG1</i> was identified. This disparity was also observed at the transcriptomic level between <i>TRPS1</i>::<i>PLAG1</i> CMTs and other tumors. However, TRPS1 immunostaining did not correlate with <i>TRPS1</i>::<i>PLAG1</i> fusion. In conclusion, we report that recurrent <i>TRPS1</i>::<i>PLAG1</i> fusion CMTs exhibit similar characteristic histological features, including tubuloductal differentiation that is associated with squamous metaplasia in around half of cases. Detection of this fusion could be valuable in correctly identifying the origin of these tumors. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"448-456"},"PeriodicalIF":5.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6359","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520563","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":"Anti-VEGFR2 neutralising antibody slows the progression of multistep oral carcinogenesis","authors":"Yoichiro Shirogane,&nbsp;Yu Usami,&nbsp;Masashi Okumura,&nbsp;Katsutoshi Hirose,&nbsp;Kohei Naniwa,&nbsp;Kazunori Ikebe,&nbsp;Satoru Toyosawa","doi":"10.1002/path.6357","DOIUrl":"10.1002/path.6357","url":null,"abstract":"<p>Angiogenesis plays an important role in cancer growth and metastasis, and it is considered a therapeutic target to control tumour growth following anti-angiogenic therapy. However, it is still unclear when tissues initiate angiogenesis during malignant transformation from premalignant condition and whether this premalignant condition could be a therapeutic target of anti-angiogenic therapy. In this study, we aimed to analyse the onset of angiogenesis by evaluating morphological and functional alterations of microvessels during oral multistep carcinogenesis using a 4-nitroquinoline 1-oxide (4NQO)-induced oral carcinogenesis mouse model. In the study, we initially confirmed that with the use of 4NQO, oral lesions develop in a stepwise manner from normal mucosa through oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC). Evaluation of CD31-immunostained specimens revealed that microvessel density (MVD) increases in a stepwise manner from OEDs. Histological and functional analyses revealed the structural abnormalities and leakage of blood vessels had already taken place in OED. Then we evaluated the expression profiles of <i>Hif1a</i> and <i>Vegfa</i> along with hypoxic status and found that OED exhibited increased <i>Vegfa</i> expression under hypoxic conditions. Finally, we tested the possibility of OEDs as a target of anti-angiogenic therapy and found that anti-VEGFR2 neutralising antibody in OED slowed the disease progression from OED to OSCC. These data indicate that an angiogenic switch occurs at the premalignant stage and morphological, and functional alterations of microvessels already exist in OED. These findings also elucidate the tumour microenvironment, which gradually develops along with carcinogenic processes, and highlight usefulness of the 4NQO-induced carcinogenesis model in the study of epithelial and stromal components, which will support epithelial carcinogenesis. © 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":"264 4","pages":"423-433"},"PeriodicalIF":5.6,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491801","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 comprehensive luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors","authors":"Ilenia Segatto,&nbsp;Maria Chiara Mattevi,&nbsp;Gian Luca Rampioni Vinciguerra,&nbsp;Nicole Crestan,&nbsp;Lorena Musco,&nbsp;Andrea Favero,&nbsp;Alessandra Dall'Acqua,&nbsp;Gabriele Di Giustino,&nbsp;Giorgia Mungo,&nbsp;Sara D'Andrea,&nbsp;Chiara Gava,&nbsp;Federica Ruggiero,&nbsp;Matteo Dugo,&nbsp;Lorenzo Gerratana,&nbsp;Fabio Puglisi,&nbsp;Samuele Massarut,&nbsp;Riccardo Bomben,&nbsp;Maurizio Callari,&nbsp;Tiziana Perin,&nbsp;Gustavo Baldassarre,&nbsp;Barbara Belletti","doi":"10.1002/path.6358","DOIUrl":"10.1002/path.6358","url":null,"abstract":"<p>Breast cancer (BC) is marked by significant genetic, morphological and clinical heterogeneity. To capture this heterogeneity and unravel the molecular mechanisms driving tumor progression and drug resistance, we established a comprehensive patient-derived xenograft (PDX) biobank, focusing particularly on luminal (estrogen receptor, ER+) and young premenopausal patients, for whom PDX models are currently scarce. Across all BC subtypes, our efforts resulted in an overall success rate of 17% (26 established PDX lines out of 151 total attempts), specifically 15% in luminal, 12% in human epidermal growth factor receptor 2 positive (HER2+) and 35% in triple negative BC. These PDX mirrored morphologic and genetic features of BC from which they originated, serving as a reliable tool to investigate drug resistance and test therapeutic strategies. We focused on understanding resistance to CDK4/6 inhibitors (CDK4/6i), which are crucial in the treatment of patients with advanced luminal BC. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumor shrinkage, some tumors might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that these PDXs have become refractory to CDK4/6i, both at biological and molecular levels, displaying significant enrichment in proliferation pathways, such as <i>MTORC1</i>, <i>E2F</i> and <i>MYC</i>. Using organoids derived from these PDX (PDxO), we observed that acquisition of CDK4/6i resistance conferred cross-resistance to endocrine therapy and that targeting MTORC1 was a successful strategy to overcome CDK4/6i resistance. Considered together, these results indicate that our PDX models may serve as robust tools to elucidate the molecular basis of BC disease progression and, by providing the possibility to simultaneously test different therapies on the same tumor, to surmount treatment resistance. While this approach is of course not feasible in the clinic, its exploitation in PDX may expedite the identification and development of more successful therapies for patients with advanced luminal BC. © 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":"264 4","pages":"434-447"},"PeriodicalIF":5.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491800","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":"Suppression of dystroglycan function accompanies pancreatic acinar-to-ductal metaplasia and favours dysplasia development","authors":"Ge Huang,&nbsp;Luke Ternes,&nbsp;Christian Lanciault,&nbsp;Kevin MacPherson-Hawthorne,&nbsp;Young Hwan Chang,&nbsp;Rosalie C Sears,&nbsp;John L Muschler","doi":"10.1002/path.6356","DOIUrl":"10.1002/path.6356","url":null,"abstract":"<p>The basement membrane (BM) is among the predominant microenvironmental factors of normal epithelia and of precancerous epithelial lesions. Evidence suggests that the BM functions not only as a barrier to tumour invasion but also as an active tumour-suppressing signalling substrate during premalignancy. However, the molecular foundations of such mechanisms have not been elucidated. Here we explore potential tumour-suppressing functions of the BM during precancer evolution, focusing on the expression and function of the extracellular matrix receptor dystroglycan in the pancreas and pancreatic disease. We show that the dystroglycan protein is highly expressed in the acinar compartment of the normal pancreas but lower in the ductal compartment. Moreover, there is a strong suppression of dystroglycan protein expression with acinar-to-ductal metaplasia in chronic pancreatitis and in all stages of pancreatic precancer and cancer evolution, from acinar-to-ductal metaplasia to dysplasia to adenocarcinoma. The conditional knockout of dystroglycan in the murine pancreas produced little evidence of developmental or functional deficiency. However, conditional deletion of dystroglycan expression in the context of oncogenic <i>Kras</i> expression led to a clear acceleration of pancreatic disease evolution, including accelerated dysplasia development and decreased survival. These data establish dystroglycan as a suppressor of pancreatic dysplasia development and one that is muted in chronic pancreatitis and at the earliest stages of oncogene-induced transformation. We conclude that dystroglycan is an important mediator of the tumour-suppressing functions of the BM during precancer evolution and that reduced dystroglycan function increases cancer risk, highlighting the dynamics of cell–BM interactions as important determinants of early cancer progression. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"411-422"},"PeriodicalIF":5.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454406","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":"Correction to ‘Hourglass, a compass navigating global and regional heterogeneity of pancreatic cancer’","authors":"","doi":"10.1002/path.6361","DOIUrl":"10.1002/path.6361","url":null,"abstract":"<p>\u0000 <span>Derya Bakırdöğen</span>, <span>Kıvanç Görgülü</span>, <span>Hana Algül</span>. <i>J Pathol</i> <span>2024</span>; <span>263</span><b>:</b> <span>5</span>–<span>7</span>. https://doi.org/10.1002/path.6268\u0000 </p><p>In this published Invited Commentary, there was an error regarding the affiliation shown for all three authors.</p><p>Instead of ‘Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, Munich, Germany’ the affiliation should have been ‘Comprehensive Cancer Center Munich TUM, Institute for Tumor Metabolism, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Bavaria, Germany’.</p><p>The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 4","pages":"457"},"PeriodicalIF":5.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454405","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}