EMBO Molecular Medicine最新文献_第3页

Melanin-like nanoparticles as a potential novel therapeutic approach in ADPKD. 黑色素样纳米粒子作为一种潜在的新型 ADPKD 治疗方法。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2025-01-01 Epub Date: 2024-11-20 DOI: 10.1038/s44321-024-00173-4

Laura Cassina, Alessandra Boletta

引用次数: 0

Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer. NOTCH和SOX2的相互抑制塑造了肿瘤细胞的可塑性和三阴性乳腺癌的治疗逃逸。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 Epub Date: 2024-10-30 DOI: 10.1038/s44321-024-00161-8

Morgane Fournier, Joaquim Javary, Vincent Roh, Nadine Fournier, Freddy Radtke

{"title":"Reciprocal inhibition of NOTCH and SOX2 shapes tumor cell plasticity and therapeutic escape in triple-negative breast cancer.","authors":"Morgane Fournier, Joaquim Javary, Vincent Roh, Nadine Fournier, Freddy Radtke","doi":"10.1038/s44321-024-00161-8","DOIUrl":"10.1038/s44321-024-00161-8","url":null,"abstract":"Cancer cell plasticity contributes significantly to the failure of chemo- and targeted therapies in triple-negative breast cancer (TNBC). Molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance are largely unknown. Using a genome-wide CRISPR-Cas9 screen, we investigated escape mechanisms of NOTCH-driven TNBC treated with a gamma-secretase inhibitor (GSI) and identified SOX2 as a target of resistance to Notch inhibition. We describe a novel reciprocal inhibitory feedback mechanism between Notch signaling and SOX2. Specifically, Notch signaling inhibits SOX2 expression through its target genes of the HEY family, and SOX2 inhibits Notch signaling through direct interaction with RBPJ. This mechanism shapes divergent cell states with NOTCH positive TNBC being more epithelial-like, while SOX2 expression correlates with epithelial-mesenchymal transition, induces cancer stem cell features and GSI resistance. To counteract monotherapy-induced tumor relapse, we assessed GSI-paclitaxel and dasatinib-paclitaxel combination treatments in NOTCH inhibitor-sensitive and -resistant TNBC xenotransplants, respectively. These distinct preventive combinations and second-line treatment option dependent on NOTCH1 and SOX2 expression in TNBC are able to induce tumor growth control and reduce metastatic burden.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3184-3217"},"PeriodicalIF":9.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. 沙门氏菌癌症疗法以 T 细胞免疫的附带代价破坏肿瘤的代谢。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 Epub Date: 2024-11-18 DOI: 10.1038/s44321-024-00159-2

Alastair Copland, Gillian M Mackie, Lisa Scarfe, Elizabeth Jinks, David A J Lecky, Nancy Gudgeon, Riahne McQuade, Masahiro Ono, Manja Barthel, Wolf-Dietrich Hardt, Hiroshi Ohno, Wilma H M Hoevenaar, Sarah Dimeloe, David Bending, Kendle M Maslowski

{"title":"Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.","authors":"Alastair Copland, Gillian M Mackie, Lisa Scarfe, Elizabeth Jinks, David A J Lecky, Nancy Gudgeon, Riahne McQuade, Masahiro Ono, Manja Barthel, Wolf-Dietrich Hardt, Hiroshi Ohno, Wilma H M Hoevenaar, Sarah Dimeloe, David Bending, Kendle M Maslowski","doi":"10.1038/s44321-024-00159-2","DOIUrl":"10.1038/s44321-024-00159-2","url":null,"abstract":"Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice (Nr4a3-Tocky-Ifnγ-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (TCM) formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3057-3088"},"PeriodicalIF":9.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers for multi-cancer detection. 将循环细胞游离线粒体 DNA 的异常片段组特征作为检测多种癌症的新型生物标记物。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 Epub Date: 2024-10-30 DOI: 10.1038/s44321-024-00163-6

Yang Liu, Fan Peng, Siyuan Wang, Huanmin Jiao, Miao Dang, Kaixiang Zhou, Wenjie Guo, Shanshan Guo, Huanqin Zhang, Wenjie Song, Jinliang Xing

{"title":"Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers for multi-cancer detection.","authors":"Yang Liu, Fan Peng, Siyuan Wang, Huanmin Jiao, Miao Dang, Kaixiang Zhou, Wenjie Guo, Shanshan Guo, Huanqin Zhang, Wenjie Song, Jinliang Xing","doi":"10.1038/s44321-024-00163-6","DOIUrl":"10.1038/s44321-024-00163-6","url":null,"abstract":"Fragmentomic features of circulating cell free mitochondrial DNA (ccf-mtDNA) including fragmentation profile, 5' end base preference and motif diversity are poorly understood. Here, we generated ccf-mtDNA sequencing data of 1607 plasma samples using capture-based next generation sequencing. We firstly found that fragmentomic features of ccf-mtDNA were remarkably different from those of circulating cell free nuclear DNA. Furthermore, region-specific fragmentomic features of ccf-mtDNA were observed, which was associated with protein binding, base composition and special structure of mitochondrial DNA. When comparing to non-cancer controls, six types of cancer patients exhibited aberrant fragmentomic features. Then, cancer detection models were built based on the fragmentomic features. Both internal and external validation cohorts demonstrated the excellent capacity of our model in distinguishing cancer patients from non-cancer control, with all area under curve higher than 0.9322. The overall accuracy of tissue-of-origin was 89.24% and 87.92% for six cancer types in two validation cohort, respectively. Altogether, our study comprehensively describes cancer-specific fragmentomic features of ccf-mtDNA and provides a proof-of-principle for the ccf-mtDNA fragmentomics-based multi-cancer detection and tissue-of-origin classification.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3169-3183"},"PeriodicalIF":9.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rett syndrome: interferon-γ to the rescue? 雷特综合征：干扰素-γ能救命吗？

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 Epub Date: 2024-11-04 DOI: 10.1038/s44321-024-00154-7

Richard R Meehan, Sari Pennings

引用次数: 0

JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia. 将 JAK-STAT1 作为表皮生长因子受体缺乏症相关炎症和瘢痕性脱发的治疗靶点。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 Epub Date: 2024-11-09 DOI: 10.1038/s44321-024-00166-3

Karoline Strobl, Jörg Klufa, Regina Jin, Lena Artner-Gent, Dana Krauß, Philipp Novoszel, Johanna Strobl, Georg Stary, Igor Vujic, Johannes Griss, Martin Holcmann, Matthias Farlik, Bernhard Homey, Maria Sibilia, Thomas Bauer

{"title":"JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia.","authors":"Karoline Strobl, Jörg Klufa, Regina Jin, Lena Artner-Gent, Dana Krauß, Philipp Novoszel, Johanna Strobl, Georg Stary, Igor Vujic, Johannes Griss, Martin Holcmann, Matthias Farlik, Bernhard Homey, Maria Sibilia, Thomas Bauer","doi":"10.1038/s44321-024-00166-3","DOIUrl":"10.1038/s44321-024-00166-3","url":null,"abstract":"The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3142-3168"},"PeriodicalIF":9.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia. 来自星形胶质细胞的 APOE 可恢复阿尔茨海默氏症 Aβ 病理学和 APOE 缺乏症小胶质细胞的 DAM 样反应。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 Epub Date: 2024-11-11 DOI: 10.1038/s44321-024-00162-7

Pranav Preman, Daan Moechars, Emre Fertan, Leen Wolfs, Lutgarde Serneels, Disha Shah, Jochen Lamote, Suresh Poovathingal, An Snellinx, Renzo Mancuso, Sriram Balusu, David Klenerman, Amaia M Arranz, Mark Fiers, Bart De Strooper

{"title":"APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia.","authors":"Pranav Preman, Daan Moechars, Emre Fertan, Leen Wolfs, Lutgarde Serneels, Disha Shah, Jochen Lamote, Suresh Poovathingal, An Snellinx, Renzo Mancuso, Sriram Balusu, David Klenerman, Amaia M Arranz, Mark Fiers, Bart De Strooper","doi":"10.1038/s44321-024-00162-7","DOIUrl":"10.1038/s44321-024-00162-7","url":null,"abstract":"The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3113-3141"},"PeriodicalIF":9.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hair follicle stem cells and the collapse of self-tolerance in alopecia: the interplay of barrier function, the microbiome, and immunity. 毛囊干细胞与脱发症自我耐受的崩溃：屏障功能、微生物组和免疫的相互作用。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 Epub Date: 2024-11-09 DOI: 10.1038/s44321-024-00170-7

Joseph S Durgin, Sunny Y Wong

引用次数: 0

Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas. 针对 ADAM12 的纤维化疫苗接种可减少临床前胰腺腺癌中的脱落细胞。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 Epub Date: 2024-10-30 DOI: 10.1038/s44321-024-00157-4

Jing Chen, Michal Sobecki, Ewelina Krzywinska, Kevin Thierry, Mélissa Masmoudi, Shunmugam Nagarajan, Zheng Fan, Jingyi He, Irina Ferapontova, Eric Nelius, Frauke Seehusen, Dagmar Gotthardt, Norihiko Takeda, Lukas Sommer, Veronika Sexl, Christian Münz, David DeNardo, Ana Hennino, Christian Stockmann

{"title":"Fibrolytic vaccination against ADAM12 reduces desmoplasia in preclinical pancreatic adenocarcinomas.","authors":"Jing Chen, Michal Sobecki, Ewelina Krzywinska, Kevin Thierry, Mélissa Masmoudi, Shunmugam Nagarajan, Zheng Fan, Jingyi He, Irina Ferapontova, Eric Nelius, Frauke Seehusen, Dagmar Gotthardt, Norihiko Takeda, Lukas Sommer, Veronika Sexl, Christian Münz, David DeNardo, Ana Hennino, Christian Stockmann","doi":"10.1038/s44321-024-00157-4","DOIUrl":"10.1038/s44321-024-00157-4","url":null,"abstract":"A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12. Previous studies have shown that immunotherapeutic ablation of ADAM12+ cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8+ T cells within the tumor and cytotoxic responses against ADAM12+ cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"3033-3056"},"PeriodicalIF":9.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11628623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Author Correction: Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases. 作者更正：通过假定的小分子抑制剂破坏 TSLP-TSLP 受体的相互作用，可为特应性疾病提供一种新颖高效的治疗方案。

IF 9 1区医学

EMBO Molecular Medicine Pub Date : 2024-12-01 DOI: 10.1038/s44321-024-00165-4

Partho Protim Adhikary, Temilolu Idowu, Zheng Tan, Christopher Hoang, Selina Shanta, Malti Dumbani, Leah Mappalakayil, Bhuwan Awasthi, Marcel Bermudez, January Weiner, Dieter Beule, Gerhard Wolber, Brent D G Page, Sarah Hedtrich

引用次数: 0