European journal of cell biology最新文献

{"title":"The expression level of VEGFR2 regulates mechanotransduction, tumor growth and metastasis of high grade serous ovarian cancer cells","authors":"Elisabetta Grillo ,&nbsp;Cosetta Ravelli ,&nbsp;Michela Corsini ,&nbsp;Mattia Domenichini ,&nbsp;Maria Scamozzi ,&nbsp;Daniela Zizioli ,&nbsp;Davide Capoferri ,&nbsp;Roberto Bresciani ,&nbsp;Chiara Romani ,&nbsp;Stefania Mitola","doi":"10.1016/j.ejcb.2024.151459","DOIUrl":"10.1016/j.ejcb.2024.151459","url":null,"abstract":"<div><div>Recent data shows that alterations in the expression and/or activation of the vascular endothelial growth factor receptor 2 (VEGFR2) in high grade serous ovarian cancer (HGSOC) modulate tumor progression. However, controversial results have been obtained, showing that in some cases VEGFR2 inhibition can promote tumorigenesis and metastasis. Thus, it is urgent to better define the role of the VEGF/VEGFR2 system to understand/predict the effects of its inhibitors administered as anti-angiogenic in HGSOC. Here, we modulated the expression levels of VEGFR2 and analyzed the effects in two cellular models of HGSOC. VEGFR2 silencing (or its pharmacological inhibition) promote the growth and invasive potential of OVCAR3 cells <em>in vitro</em> and <em>in vivo</em>. Consistent with this, the low levels of VEGFR2 in OV7 cells are associated with more pronounced proliferative and motile phenotypes when compared to OVCAR3 cells, and VEGFR2 overexpression in OV7 cells inhibits cell growth. <em>In vitro</em> data confirmed that VEGFR2 silencing in OVCAR3 cells favors the acquisition of an invasive phenotype by loosening cell-ECM contacts, reducing the size and the signaling of focal adhesion contacts (FAs). This is translated into a reduced FAK activity at FAs, ECM-dependent alterations of mechanical forces through FAs and YAP nuclear translocation. Together, the data show that low expression, silencing or inhibition of VEGFR2 in HGSOC cells alter mechanotransduction and lead to the acquisition of a pro-proliferative/invasive phenotype which explains the need for a more cautious use of anti-VEGFR2 drugs in ovarian cancer.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151459"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK activity regulates mesoderm cell fate by controlling MESP1 expression","authors":"Su Yao ,&nbsp;Yalin Zhu ,&nbsp;Fenglian He ,&nbsp;Min Yuan ,&nbsp;Rui Jiang ,&nbsp;Hongjie Zhang ,&nbsp;Yanbin Fu ,&nbsp;Ke Wei","doi":"10.1016/j.ejcb.2024.151452","DOIUrl":"10.1016/j.ejcb.2024.151452","url":null,"abstract":"<div><p>Cardiac development requires precise gene expression programs at each developmental stage guided by multiple signaling pathways and transcription factors (TFs). MESP1 is transiently expressed in mesoderm, and is essential for subsequent cardiac development, while the precise mechanism regulating its own transcription and mesoderm cell fate is not fully understood. Therefore, we developed a high content screen assay to identify regulators of MESP1 expression in mesodermal cells differentiated from human pluripotent stem cells (hPSCs). The screen identified CYT387, a JAK1/JAK2 kinase inhibitor, as a potent activator of MESP1 expression, which was also found to promote cardiomyocyte differentiation <em>in vitro</em>. Mechanistic studies found that JAK inhibition promotes MESP1 expression by reducing cytoplasmic calcium concentration and subsequently activating canonical WNT signaling. Our study identified a role of JAK signaling in early mesodermal cells, and sheds light on the connection between the JAK-STAT pathway and transcriptional regulation of MESP1, which expands our understanding of mesoderm and cardiac development.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151452"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000694/pdfft?md5=52f210f6e16efdf5868a374965a7a6ba&pid=1-s2.0-S0171933524000694-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142050283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial overview: EJCB Special Issue – Cell host-pathogen interactions","authors":"Serge Mostowy ,&nbsp;Theresia E.B. Stradal","doi":"10.1016/j.ejcb.2024.151462","DOIUrl":"10.1016/j.ejcb.2024.151462","url":null,"abstract":"","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151462"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased mTOR activity and RICTOR copy number in small cell lung carcinoma progression","authors":"Dániel Sztankovics ,&nbsp;Fatime Szalai ,&nbsp;Dorottya Moldvai ,&nbsp;Titanilla Dankó ,&nbsp;Noémi Nagy ,&nbsp;Judit Pápay ,&nbsp;András Khoór ,&nbsp;Ildikó Krencz ,&nbsp;Anna Sebestyén","doi":"10.1016/j.ejcb.2024.151468","DOIUrl":"10.1016/j.ejcb.2024.151468","url":null,"abstract":"<div><div>Small cell lung carcinoma (SCLC) is a highly malignant cancer with early metastatic dissemination and poor clinical outcomes. Mutations in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, including the frequently occurring rapamycin-insensitive protein (<em>RICTOR</em>) amplification, have been described in these tumours. Moreover, the associated mTOR hyperactivity could be exploited for personalised treatment. Our aim was to study mTOR activity, <em>RICTOR</em> amplification, and their role during SCLC progression. <em>In situ</em> mTOR activity and Rictor expression were characterised by immunohistochemistry in 50 primary and 50 brain metastatic tumours, and 14 paired SCLC patient samples. <em>RICTOR</em> copy number changes were analysed by fluorescence <em>in situ</em> hybridisation of the paired SCLC patient samples and <em>in vivo</em> experiments. Additionally, <em>in vitro</em> sensitivity to cisplatin and mTOR inhibitors was evaluated in SCLC cell lines harbouring <em>RICTOR</em> amplification and other mTOR pathway mutations. High Rictor expression and mTOR complex 2 (mTORC2) hyperactivity were significantly associated with brain metastases and worse overall survival. An increase in <em>RICTOR</em> copy number was observed in paired samples during progression. The importance of these alterations was confirmed both by the sensitising effect of vistusertib <em>in vitro</em> and the <em>RICTOR</em> copy number/expression changes in xenografts. Our study highlights the role of mTORC2 in SCLC progression. Early detection of <em>RICTOR</em> amplification in primary tumours and targeting mTORC2 in these cases may represent a promising novel strategy to develop personalised therapy for metastasis prevention.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151468"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the development and evolution of the mammalian cerebrum using gyrencephalic ferrets","authors":"Masanori Imamura ,&nbsp;Mayuko Yoshino ,&nbsp;Hiroshi Kawasaki","doi":"10.1016/j.ejcb.2024.151466","DOIUrl":"10.1016/j.ejcb.2024.151466","url":null,"abstract":"<div><div>Mammalian brains have evolved a neocortex, which has diverged in size and morphology in different species over the course of evolution. In some mammals, a substantial increase in the number of neurons and glial cells resulted in the expansion and folding of the cerebrum, and it is believed that these evolutionary changes contributed to the acquisition of higher cognitive abilities in mammals. However, their underlying molecular and cellular mechanisms remain insufficiently elucidated. A major difficulty in addressing these mechanisms stemmed from the lack of appropriate animal models, as conventional experimental animals such as mice and rats have small brains without structurally obvious folds. Therefore, researchers including us have focused on using ferrets instead of mice and rats. Ferrets are domesticated carnivorous mammals with a gyrencephalic cerebrum, and, notably, they are amenable to genetic manipulations including <em>in utero</em> electroporation to knock out genes in the cerebrum. In this review, we highlight recent research into the mechanisms underlying the development and evolution of cortical folds using ferrets.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151466"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salmonella infection impacts host proteome thermal stability","authors":"Marlène S. Birk ,&nbsp;Philipp Walch ,&nbsp;Tarik Baykara ,&nbsp;Stephanie Sefried ,&nbsp;Jan Amelang ,&nbsp;Elena Buerova ,&nbsp;Ingrid Breuer ,&nbsp;Jörg Vervoorts ,&nbsp;Athanasios Typas ,&nbsp;Mikhail M. Savitski ,&nbsp;André Mateus ,&nbsp;Joel Selkrig","doi":"10.1016/j.ejcb.2024.151448","DOIUrl":"10.1016/j.ejcb.2024.151448","url":null,"abstract":"<div><p>Intracellular bacterial pathogens hijack the protein machinery of infected host cells to evade their defenses and cultivate a favorable intracellular niche. The intracellular pathogen <em>Salmonella enterica</em> subsp. Typhimurium (<em>S</em>Tm) achieves this by injecting a cocktail of effector proteins into host cells that modify the activity of target host proteins. Yet, proteome-wide approaches to systematically map changes in host protein function during infection have remained challenging. Here we adapted a functional proteomics approach - Thermal-Proteome Profiling (TPP) - to systematically assess proteome-wide changes in host protein abundance and thermal stability throughout an <em>S</em>Tm infection cycle. By comparing macrophages treated with live or heat-killed <em>S</em>Tm, we observed that most host protein abundance changes occur independently of <em>S</em>Tm viability. In contrast, a large portion of host protein thermal stability changes were specific to infection with live <em>S</em>Tm. This included pronounced thermal stability changes in proteins linked to mitochondrial function (Acod1/Irg1, Cox6c, Samm50, Vdac1, and mitochondrial respiratory chain complex proteins), as well as the interferon-inducible protein with tetratricopeptide repeats, Ifit1. Integration of our TPP data with a publicly available <em>S</em>Tm-host protein-protein interaction database led us to discover that the secreted <em>S</em>Tm effector kinase, SteC, thermally destabilizes and phosphorylates the ribosomal preservation factor Serbp1. In summary, this work emphasizes the utility of measuring protein thermal stability during infection to accelerate the discovery of novel molecular interactions at the host-pathogen interface.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151448"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000657/pdfft?md5=0165df0c33e474067e594538a5fed8cd&pid=1-s2.0-S0171933524000657-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generating kidney organoids based on developmental nephrology","authors":"Yutaro Ibi,&nbsp;Ryuichi Nishinakamura","doi":"10.1016/j.ejcb.2024.151450","DOIUrl":"10.1016/j.ejcb.2024.151450","url":null,"abstract":"<div><p>Over the past decade, the induction protocols for the two types of kidney organoids (nephron organoids and ureteric bud organoids) from pluripotent stem cells (PSCs) have been established based on the knowledge gained in developmental nephrology. Kidney organoids are now used for disease modeling and drug screening, but they also have potential as tools for clinical transplantation therapy. One of the options to achieve this goal would be to assemble multiple renal progenitor cells (nephron progenitor, ureteric bud, stromal progenitor) to reproduce the organotypic kidney structure from PSCs. At least from mouse PSCs, all the three progenitors have been induced and assembled into such “higher order” kidney organoids. We will provide an overview of the developmental nephrology required for the induction of renal progenitors and discuss recent advances and remaining challenges of kidney organoids for clinical transplantation therapy.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151450"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000670/pdfft?md5=19fbc7d41b11a8bbb7a13ed75c5ac68f&pid=1-s2.0-S0171933524000670-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"dCas9-HDAC8-EGFP fusion enables epigenetic editing of breast cancer cells by H3K9 deacetylation","authors":"Mohammad Mijanur Rahman ,&nbsp;Trygve O. Tollefsbol","doi":"10.1016/j.ejcb.2024.151463","DOIUrl":"10.1016/j.ejcb.2024.151463","url":null,"abstract":"<div><div>Epigenetic editing is thriving as a robust tool for manipulating transcriptional regulation and cell fate. Despite its regulatory role in gene downregulation, epigenetic editing with histone deacetylation has been sparsely studied, especially in the context of cancer. In this current study, we have reconstructed a dCas9-HDAC8-EGFP fusion to perform histone deacetylation on the promoter of the <em>ESR1</em>, <em>TERT</em> and <em>CDKN1C</em> genes for the first time in breast cancer cell lines MCF-7 and MDA-MB-231 as well as in HEK293T cells. Our results demonstrated that dCas9-HDAC8-EGFP in combination with appropriate gRNAs were able to downregulate the expression of the <em>ESR1</em>, <em>TERT</em> and <em>CDKN1C</em> genes transcriptionally by specifically depleting the H3K9ac level on the recruitment loci. The addition of histone deacetylase inhibitors was found to neutralize the outcomes of dCas9-HDAC8-EGFP-induced epigenetic editing. Furthermore, we observed a significant downregulation of full length ERα expression in epigenetically edited MCF-7 cells with consequential alteration in cellular response toward estradiol and tamoxifen treatment due to dCas9-HDAC8-EGFP mediated epigenetic editing of the <em>ESR1</em> gene. Overall, dCas9-HDAC8-EGFP is a novel circuit that enabled downregulation of crucial genes with cellular outcome in breast cancer cells by preferentially inducing H3K9 deacetylation of specific promoter regions.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151463"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of cholesterol biosynthesis by CTCF and H3K27 methylation is critical for cell migration","authors":"Lukasz Stanislaw Kaczmarczyk ,&nbsp;Dagmawit Babele ,&nbsp;Nehora Levi ,&nbsp;Gowthaman Gunasekaran ,&nbsp;Mali Salmon-Divon ,&nbsp;Gabi Gerlitz","doi":"10.1016/j.ejcb.2024.151454","DOIUrl":"10.1016/j.ejcb.2024.151454","url":null,"abstract":"<div><p>CTCF is a key factor in three-dimensional chromatin folding and transcriptional control that was found to affect cancer cell migration by a mechanism that is still poorly understood. To identify this mechanism, we used mouse melanoma cells with a partial loss of function (pLoF) of CTCF. We found that CTCF pLoF inhibits cell migration rate while leading to an increase in the expression of multiple enzymes in the cholesterol biosynthesis pathway along with an elevation in the cellular cholesterol level. In agreement with the cholesterol change we detected altered membrane dynamics in CTCF pLoF cells as measured by reduced formation of migrasomes, extracellular vesicles formed at the rear side of migrating cells. Inhibition of cholesterol synthesis in CTCF pLoF cells restored the cellular migration rate and migrasome formation, suggesting that CTCF supports cell migration by suppressing cholesterol synthesis. Detailed analysis of the promoter of <em>Hmgcs1</em>, an early enzyme in the cholesterol synthesis pathway, revealed that CTCF prevents formation of a loop between that promoter and another promoter 200 kb away. CTCF also supports PRC2 recruitment to the promoter and deposition of H3K27me3. H3K27me3 at the promoter of <em>Hmgcs1</em> prevents SREBP2 binding and activation of transcription. By this mechanism, CTCF fine-tunes cholesterol levels to support cell migration. Notably, genome wide association studies suggest a link between CTCF and cholesterol-associated diseases, thus CTCF emerges as a new regulator of cholesterol biosynthesis.</p></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151454"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0171933524000712/pdfft?md5=0577d7a701c222841e742a834060ce91&pid=1-s2.0-S0171933524000712-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142129020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin receptor substrate 1 is a novel member of EGFR signaling in pancreatic cells","authors":"Tamás Takács ,&nbsp;Loretta László ,&nbsp;Álmos Tilajka ,&nbsp;Julianna Novák ,&nbsp;László Buday ,&nbsp;Virag Vas","doi":"10.1016/j.ejcb.2024.151457","DOIUrl":"10.1016/j.ejcb.2024.151457","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma is an extremely incurable cancer type characterized by cells with highly proliferative capacity and resistance against the current therapeutic options. Our study reveals that IRS1 acts as a bridging molecule between EGFR and IGFR/InsR signalization providing a potential mechanism for the interplay between signaling pathways and bypassing EGFR-targeted or IGFR/InsR-targeted therapies. The analysis of IRS1 phosphorylation status in four pancreatic cell lines identified the impact of EGFR signaling on IRS1 activation in comparison with InsR/IGFR signaling. Significantly reduced viability was observed in IRS1-silenced cells even upon EGF stimulation showing the critical role of IRS1 in the EGFR signaling network in both malignant and normal pancreatic cells. This study also demonstrated that EGFR binds directly to IRS1 and at least on two tyrosine sites, Y612 and Y896, IRS1 becomes phosphorylated in response to EGF stimulation. Mechanistically, the EGFR-mediated phosphorylation of IRS1 can further activate the MAPK signaling pathway with the recruitment of GRB2 protein. Collectively, in this study, IRS1 was identified as a crucial regulator in the EGFR signaling suggesting IRS1 as a potential target for more durable responses to targeted PDAC therapy.</div></div>","PeriodicalId":12010,"journal":{"name":"European journal of cell biology","volume":"103 4","pages":"Article 151457"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}