The Journal of Pathology最新文献

{"title":"Development of a multi-scanner facility for data acquisition for digital pathology artificial intelligence","authors":"Matthew P Humphries,&nbsp;Danny Kaye,&nbsp;Gaby Stankeviciute,&nbsp;Jacob Halliwell,&nbsp;Alexander I Wright,&nbsp;Daljeet Bansal,&nbsp;David Brettle,&nbsp;Darren Treanor","doi":"10.1002/path.6326","DOIUrl":"10.1002/path.6326","url":null,"abstract":"<p>Whole slide imaging (WSI) of pathology glass slides using high-resolution scanners has enabled the large-scale application of artificial intelligence (AI) in pathology, to support the detection and diagnosis of disease, potentially increasing efficiency and accuracy in tissue diagnosis. Despite the promise of AI, it has limitations. ‘Brittleness’ or sensitivity to variation in inputs necessitates that large amounts of data are used for training. AI is often trained on data from different scanners but not usually by replicating the same slide across scanners. The utilisation of multiple WSI instruments to produce digital replicas of the same slides will make more comprehensive datasets and may improve the robustness and generalisability of AI algorithms as well as reduce the overall data requirements of AI training. To this end, the National Pathology Imaging Cooperative (NPIC) has built the AI FORGE (Facilitating Opportunities for Robust Generalisable data Emulation), a unique multi-scanner facility embedded in a clinical site in the NHS to (1) compare scanner performance, (2) replicate digital pathology image datasets across WSI systems, and (3) support the evaluation of clinical AI algorithms. The NPIC AI FORGE currently comprises 15 scanners from nine manufacturers. It can generate approximately 4,000 WSI images per day (approximately 7 TB of image data). This paper describes the process followed to plan and build such a facility. © 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 1","pages":"80-89"},"PeriodicalIF":5.6,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6326","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The genomic trajectory of ovarian high-grade serous carcinoma can be observed in STIC lesions","authors":"Zhao Cheng,&nbsp;Darren P Ennis,&nbsp;Bingxin Lu,&nbsp;Hasan B Mirza,&nbsp;Chishimba Sokota,&nbsp;Baljeet Kaur,&nbsp;Naveena Singh,&nbsp;Olivia Le Saux,&nbsp;Giorgia Russo,&nbsp;Gaia Giannone,&nbsp;Laura A Tookman,&nbsp;Jonathan Krell,&nbsp;Chris Barnes,&nbsp;Jackie McDermott,&nbsp;Iain A McNeish","doi":"10.1002/path.6322","DOIUrl":"10.1002/path.6322","url":null,"abstract":"<p>Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a <i>TP53</i> mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole-genome duplication (WGD) observed in late-stage disease were determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole-genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next-generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises early in HGSC and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development. © 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 1","pages":"42-54"},"PeriodicalIF":5.6,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490296","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":"Air pollution aggravates renal ischaemia–reperfusion-induced acute kidney injury","authors":"Talita Rojas Sanches,&nbsp;Antonio Carlos Parra,&nbsp;Peiqi Sun,&nbsp;Mariana Pereira Graner,&nbsp;Lucas Yuji Umesaki Itto,&nbsp;Loes Maria Butter,&nbsp;Nike Claessen,&nbsp;Joris JTH Roelofs,&nbsp;Sandrine Florquin,&nbsp;Mariana Matera Veras,&nbsp;Maria de Fatima Andrade,&nbsp;Paulo Hilário Nascimento Saldiva,&nbsp;Jesper Kers,&nbsp;Lucia Andrade,&nbsp;Alessandra Tammaro","doi":"10.1002/path.6302","DOIUrl":"10.1002/path.6302","url":null,"abstract":"<p>Chronic kidney disease (CKD) has emerged as a significant global public health concern. Recent epidemiological studies have highlighted the link between exposure to fine particulate matter (PM_2.5) and a decline in renal function. PM_2.5 exerts harmful effects on various organs through oxidative stress and inflammation. Acute kidney injury (AKI) resulting from ischaemia–reperfusion injury (IRI) involves biological processes similar to those involved in PM_2.5 toxicity and is a known risk factor for CKD. The objective of this study was to investigate the impact of PM_2.5 exposure on IRI-induced AKI. Through a unique environmentally controlled setup, mice were exposed to urban PM_2.5 or filtered air for 12 weeks before IRI followed by euthanasia 48 h after surgery. Animals exposed to PM_2.5 and IRI exhibited reduced glomerular filtration, impaired urine concentration ability, and significant tubular damage. Further, PM_2.5 aggravated local innate immune responses and mitochondrial dysfunction, as well as enhancing cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) pathway activation. This increased renal senescence and suppressed the anti-ageing protein klotho, leading to early fibrotic changes. <i>In vitro</i> studies using proximal tubular epithelial cells exposed to PM_2.5 and hypoxia/reoxygenation revealed heightened activation of the STING pathway triggered by cytoplasmic mitochondrial DNA, resulting in increased tubular damage and a pro-inflammatory phenotype. In summary, our findings imply a role for PM_2.5 in sensitising proximal tubular epithelial cells to IRI-induced damage, suggesting a plausible association between PM_2.5 exposure and heightened susceptibility to CKD in individuals experiencing AKI. Strategies aimed at reducing PM_2.5 concentrations and implementing preventive measures may improve outcomes for AKI patients and mitigate the progression from AKI to CKD. © 2024 The Authors. <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":"263 4-5","pages":"496-507"},"PeriodicalIF":5.6,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454301","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":"Interaction of the tumor suppressor SMAD4 and WNT signaling in progression to oral squamous cell carcinoma","authors":"Jing Yang,&nbsp;James S Lewis,&nbsp;Jinghuan Zi,&nbsp;Thomas Andl,&nbsp;Ethan Lee,&nbsp;Claudia D Andl,&nbsp;Qi Liu,&nbsp;Robert D Beauchamp,&nbsp;Anna L Means","doi":"10.1002/path.6318","DOIUrl":"10.1002/path.6318","url":null,"abstract":"<p>SMAD4 is a tumor suppressor mutated or silenced in multiple cancers, including oral cavity squamous cell carcinoma (OSCC). Human clinical samples and cell lines, mouse models and organoid culture were used to investigate the role that SMAD4 plays in progression from benign disease to invasive OSCC. Human OSCC lost detectable SMAD4 protein within tumor epithelium in 24% of cases, and this loss correlated with worse progression-free survival independent of other major clinical and pathological features. A mouse model engineered for <i>Kras</i>^G12D expression in the adult oral epithelium induced benign papillomas, however the combination of <i>Kras</i>^G12D with loss of epithelial <i>Smad4</i> expression resulted in rapid development of invasive carcinoma with features of human OSCC. Examination of regulatory pathways in 3D organoid cultures of SMAD4+ and SMAD4− mouse tumors with <i>Kras</i> mutation found that either loss of SMAD4 or inhibition of TGFβ signaling upregulated the WNT pathway and altered the extracellular matrix. The gene signature of the mouse tumor organoids lacking SMAD4 was highly similar to the gene signature of human head and neck squamous cell carcinoma. In summary, this work has uncovered novel mechanisms by which SMAD4 acts as a tumor suppressor in OSCC. © 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 1","pages":"4-16"},"PeriodicalIF":5.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454302","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":"Liver-specific DICER1 syndrome model mice develop cystic liver tumors with defective primary cilia","authors":"Keiki Oikawa,&nbsp;Shin-ichiro Ohno,&nbsp;Kana Ono,&nbsp;Kaito Hirao,&nbsp;Ayano Murakami,&nbsp;Yuichirou Harada,&nbsp;Katsuyoshi Kumagai,&nbsp;Katsuko Sudo,&nbsp;Masakatsu Takanashi,&nbsp;Akio Ishikawa,&nbsp;Shouichirou Mineo,&nbsp;Koji Fujita,&nbsp;Tomohiro Umezu,&nbsp;Noriko Watanabe,&nbsp;Yoshiki Murakami,&nbsp;Shinichiro Ogawa,&nbsp;Kris Ann Schultz,&nbsp;Masahiko Kuroda","doi":"10.1002/path.6320","DOIUrl":"10.1002/path.6320","url":null,"abstract":"<p>DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in <i>DICER1</i>. Pathogenic variants of <i>DICER1</i> have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that <i>DICER1</i> mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by <i>DICER1</i> variants and for obtaining a comprehensive understanding of DICER1 syndrome. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"264 1","pages":"17-29"},"PeriodicalIF":5.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454303","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":"The E3 ubiquitin ligase TRIP12 is required for pancreatic acinar cell plasticity and pancreatic carcinogenesis","authors":"Manon Brunet,&nbsp;Claire Vargas,&nbsp;Marjorie Fanjul,&nbsp;Damien Varry,&nbsp;Naïma Hanoun,&nbsp;Dorian Larrieu,&nbsp;Laetitia Pieruccioni,&nbsp;Guillaume Labrousse,&nbsp;Hubert Lulka,&nbsp;Florence Capilla,&nbsp;Alban Ricard,&nbsp;Janick Selves,&nbsp;Anne Couvelard,&nbsp;Véronique Gigoux,&nbsp;Pierre Cordelier,&nbsp;Julie Guillermet-Guibert,&nbsp;Marlène Dufresne,&nbsp;Jérôme Torrisani","doi":"10.1002/path.6298","DOIUrl":"10.1002/path.6298","url":null,"abstract":"<p>The E3 ubiquitin ligase thyroid hormone receptor interacting protein 12 (TRIP12) has been implicated in pancreatic adenocarcinoma (PDAC) through its role in mediating the degradation of pancreas transcription factor 1a (PTF1a). PTF1a is a transcription factor essential for the acinar differentiation state that is notably diminished during the early steps of pancreatic carcinogenesis. Despite these findings, the direct involvement of TRIP12 in the onset of pancreatic cancer has yet to be established. In this study, we demonstrated that TRIP12 protein was significantly upregulated in human pancreatic preneoplastic lesions. Furthermore, we observed that TRIP12 overexpression varied within PDAC samples and PDAC-derived cell lines. We further demonstrated that TRIP12 was required for PDAC-derived cell growth and for the expression of E2F-targeted genes. Acinar-to-ductal cell metaplasia (ADM) is a reversible process that reflects the high plasticity of acinar cells. ADM becomes irreversible in the presence of oncogenic <i>Kras</i> mutations and leads to the formation of preneoplastic lesions. Using two genetically modified mouse models, we showed that a loss of TRIP12 prevented acini from developing ADM in response to pancreatic injury. With two additional mouse models, we further discovered that a depletion of TRIP12 prevented the formation of Kras^G12D-induced preneoplastic lesions and impaired metastasis formation in the presence of mutated <i>Kras</i>^G12D and <i>Trp53</i>^R172H genes. In summary our study identified an overexpression of TRIP12 from the early stages of pancreatic carcinogenesis and proposed this E3 ubiquitin ligase as a novel regulator of acinar plasticity with an important dual role in initiation and metastatic steps of PDAC. © 2024 The Authors. <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":"263 4-5","pages":"466-481"},"PeriodicalIF":5.6,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6298","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454273","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":"Novel chemokine biomarkers in melanoma†","authors":"Alessio Giubellino,&nbsp;Sara E Hamilton","doi":"10.1002/path.6323","DOIUrl":"10.1002/path.6323","url":null,"abstract":"<p>The melanoma tumor microenvironment is a complex milieu of cancer, inflammatory, and stromal cells. In this context, chemokines play a pivotal role in recruiting inflammatory cells and influence the tumor, exerting both pro-tumorigenic and anti-tumoral roles. Interactions between these cells is what ultimately hold together and transform the tumor into an efficient machine. A recent study found that chemokines CCL8, CCL15, and CCL20 were upregulated in melanoma cells when co-cultured with macrophages and were associated with poor survival rates. CCL8 and CCL15 also stimulated melanoma cell growth, invasion, and metastasis, and were highly expressed in tumors prone to metastasize, suggesting these chemokines are attractive and independent biomarkers. Understanding the intricated interactions within the tumor microenvironment could lead to prognostic biomarkers and to the development of new therapeutic strategies for melanoma. © 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 1","pages":"1-3"},"PeriodicalIF":5.6,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141454272","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":"Agalactosyl IgG induces liver fibrogenesis via Fc gamma receptor 3a on human hepatic stellate cells","authors":"Cheng-Hsun Ho,&nbsp;Ting-Tsung Chang,&nbsp;Hsien-Chang Lin,&nbsp;Sheng-Fan Wang","doi":"10.1002/path.6303","DOIUrl":"10.1002/path.6303","url":null,"abstract":"<p>The relevance of aberrant serum IgG <i>N</i>-glycosylation in liver fibrosis has been identified; however, its causal effect remains unclear. Because hepatic stellate cells (HSCs) contribute substantially to liver fibrosis, we investigated whether and through which mechanisms IgG <i>N</i>-glycosylation affects the fibrogenic properties of HSCs. Analysis of serum IgG₁ <i>N</i>-glycome from 151 patients with chronic hepatitis B or liver cirrhosis revealed a positive correlation between Ishak fibrosis grading and IgG₁ with agalactosyl <i>N</i>-glycoforms on the crystallizable fragment (Fc). Fc gamma receptor (FcγR) IIIa was observed in cultured human HSCs and HSCs in human liver tissues, and levels of FcγRIIIa in HSCs correlated with the severity of liver fibrosis. Additionally, agalactosyl IgG treatment caused HSCs to have a fibroblast-like morphology, enhanced migration and invasion capabilities, and enhanced expression of the FcγRIIIa downstream tyrosine-protein kinase SYK. Furthermore, agalactosyl IgG treatment increased fibrogenic factors in HSCs, including transforming growth factor (TGF)-β1, total collagen, platelet-derived growth factor subunit B and its receptors, pro-collagen I-α1, α-smooth muscle actin, and matrix metalloproteinase 9. These effects were more pronounced in HSCs that stably expressed <i>FCGR3A</i> and were reduced in <i>FCGR3A</i> knockout cells. Agalactosyl IgG and TGF-β1 each increased <i>FCGR3A</i> in HSCs. Furthermore, serum TGF-β1 concentrations in patients were positively correlated with agalactosyl IgG₁ levels and liver fibrosis severity, indicating a positive feedback loop involving agalactosyl IgG, HSC-FcγRIIIa, and TGF-β1. In conclusion, agalactosyl IgG promotes fibrogenic characteristics in HSCs through FcγRIIIa. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 4-5","pages":"508-519"},"PeriodicalIF":5.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417050","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":"The emerging role of targeted protein degradation to treat and study cancer","authors":"Maximillian H Brodermann,&nbsp;Elizabeth K Henderson,&nbsp;Rob S Sellar","doi":"10.1002/path.6301","DOIUrl":"10.1002/path.6301","url":null,"abstract":"<p>The evolution of cancer treatment has provided increasingly targeted strategies both in the upfront and relapsed disease settings. Small-molecule inhibitors and immunotherapy have risen to prominence with chimeric antigen receptor T-cells, checkpoint inhibitors, kinase inhibitors, and monoclonal antibody therapies being deployed across a range of solid organ and haematological malignancies. However, novel approaches are required to target transcription factors and oncogenic fusion proteins that are central to cancer biology and have generally eluded successful drug development. Thalidomide analogues causing protein degradation have been a cornerstone of treatment in multiple myeloma, but a lack of in-depth mechanistic understanding initially limited progress in the field. When the protein cereblon (CRBN) was found to mediate thalidomide analogues' action and CRBN's neo-targets were identified, existing and novel drug development accelerated, with applications outside multiple myeloma, including non-Hodgkin's lymphoma, myelodysplastic syndrome, and acute leukaemias. Critically, transcription factors were the first canonical targets described. In addition to broadening the application of protein-degrading drugs, resistance mechanisms are being overcome and targeted protein degradation is widening the scope of druggable proteins against which existing approaches have been ineffective. Examples of targeted protein degraders include molecular glues and proteolysis targeting chimeras (PROTACs): heterobifunctional molecules that bind to proteins of interest and cause proximity-induced ubiquitination and proteasomal degradation <i>via</i> a linked E3 ligase. Twenty years since their inception, PROTACs have begun progressing through clinical trials, with early success in targeting the oestrogen receptor and androgen receptor in breast and prostate cancer respectively. This review explores important developments in targeted protein degradation to both treat and study cancer. It also considers the potential advantages and challenges in the translational aspects of developing new treatments. © 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":"263 4-5","pages":"403-417"},"PeriodicalIF":5.6,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141417051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche","authors":"Ester Gonzalez-Sanchez,&nbsp;Javier Vaquero,&nbsp;Daniel Caballero-Diaz,&nbsp;Jan Grzelak,&nbsp;Noel P Fusté,&nbsp;Esther Bertran,&nbsp;Josep Amengual,&nbsp;Juan Garcia-Saez,&nbsp;Beatriz Martín-Mur,&nbsp;Marta Gut,&nbsp;Anna Esteve-Codina,&nbsp;Ania Alay,&nbsp;Cedric Coulouarn,&nbsp;Silvia Calero-Perez,&nbsp;Pilar Valdecantos,&nbsp;Angela M Valverde,&nbsp;Aránzazu Sánchez,&nbsp;Blanca Herrera,&nbsp;Isabel Fabregat","doi":"10.1002/path.6299","DOIUrl":"10.1002/path.6299","url":null,"abstract":"<p>Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl₄), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl₄-treated ΔEGFR mice when compared with CCl₄-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from <i>in vitro</i> experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. <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":"263 4-5","pages":"482-495"},"PeriodicalIF":5.6,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316232","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}