EMBO Molecular Medicine最新文献

{"title":"Boosting human immunology: harnessing the potential of immune organoids.","authors":"Maximilian Moll, Dirk Baumjohann","doi":"10.1038/s44321-025-00193-8","DOIUrl":"10.1038/s44321-025-00193-8","url":null,"abstract":"<p><p>Studying the human immune system in vivo is challenging and often not possible. Therefore, most human immunology studies have been predominantly confined to peripheral blood analyses, which by themselves have inherent limitations, as many immune reactions take place within tissues. For example, potent antibody responses that contribute to fighting infections and provide protection following vaccination require cellular interactions between B cells and T cells in specialized micro-anatomical structures called germinal centers, which are found in secondary lymphoid organs such as spleen, lymph nodes, and tonsils. Thus, there is a clear demand for novel enhanced experimental systems that faithfully recapitulate the intricate dynamics of the human immune system as much as possible. In this review, we discuss recent advances in versatile human tonsil/adenoid tissue-based ex vivo immune organoid cultures as well as related cancer and autoimmunity-focused experimental setups. These systems have been implemented as translational immunology platforms for in-depth analyses of human B and T cell-mediated immune responses, thereby facilitating mechanistic studies as well as drug and vaccine testing in a human-first approach.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"385-394"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052071","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}

{"title":"An AI-assisted morphoproteomic approach is a supportive tool in esophagitis-related precision medicine.","authors":"Sven Mattern, Vanessa Hollfoth, Eyyub Bag, Arslan Ali, Philip Riemenschneider, Mohamed A Jarboui, Karsten Boldt, Mihaly Sulyok, Anabel Dickemann, Julia Luibrand, Stefano Fusco, Mirita Franz-Wachtel, Kerstin Singer, Benjamin Goeppert, Oliver Schilling, Nisar Malek, Falko Fend, Boris Macek, Marius Ueffing, Stephan Singer","doi":"10.1038/s44321-025-00194-7","DOIUrl":"10.1038/s44321-025-00194-7","url":null,"abstract":"<p><p>Esophagitis is a frequent, but at the molecular level poorly characterized condition with diverse underlying etiologies and treatments. Correct diagnosis can be challenging due to partially overlapping histological features. By proteomic profiling of routine diagnostic FFPE biopsy specimens (n = 55) representing controls, Reflux- (GERD), Eosinophilic-(EoE), Crohn's-(CD), Herpes simplex (HSV) and Candida (CA)-esophagitis by LC-MS/MS (DIA), we identified distinct signatures and functional networks (e.g. mitochondrial translation (EoE), immunoproteasome, complement and coagulations system (CD), ribosomal biogenesis (GERD)), and pathogen-specific proteins for HSV and CA. Moreover, combining these signatures with histological parameters in a machine learning model achieved high diagnostic accuracy (100% training set, 93.8% test set), and supported diagnostic decisions in borderline/challenging cases. Applied to a young patient representing a use case, the external GERD diagnosis could be revised to CD and ICAM1 was identified as highly abundant therapeutic target. This resulted in CyclosporinA as a personalized treatment recommendation by the local multidisciplinary molecular inflammation board. Our integrated AI-assisted morphoproteomic approach allows deeper insights in disease-specific molecular alterations and represents a promising tool in esophagitis-related precision medicine.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"441-468"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122538","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}

{"title":"Repression of apelin Furin cleavage sites provides antimetastatic strategy in colorectal cancer.","authors":"Béatrice Demoures, Fabienne Soulet, Jean Descarpentrie, Isabel Galeano-Otero, José Sanchez Collado, Maria Casado, Tarik Smani, Alvaro González, Isabel Alves, Fabrice Lalloué, Bernard Masri, Estelle Rascol, Jean-William Dupuy, Cyril Dourthe, Frédéric Saltel, Anne-Aurélie Raymond, Iker Badiola, Serge Evrard, Bruno Villoutreix, Simon Pernot, Géraldine Siegfried, Abdel-Majid Khatib","doi":"10.1038/s44321-025-00196-5","DOIUrl":"10.1038/s44321-025-00196-5","url":null,"abstract":"<p><p>The adipokine apelin has been directly implicated in various physiological processes during embryogenesis and human cancers. Nevertheless, the importance of the conversion of its precursor proapelin to mature apelin in tumorigenesis remains unknown. In this study, we identify Furin as the cellular proprotein convertase responsible for proapelin cleavage. We explore the therapeutic potential of targeting proapelin cleavage sites in metastatic colorectal cancer by introducing apelin-dm, a modified variant resulting from alteration in proapelin cleavage sites. Apelin-dm demonstrates efficacy in inhibiting tumor growth, promoting cell death, suppressing angiogenesis, and early colorectal liver metastasis events. Proteomic analysis reveals reciprocal regulation between apelin and apelin-dm on proteins associated with clinical outcomes in colon cancer patients. Apelin-dm emerges as a modulator of apelin receptor dynamics, influencing affinity, internalization, and repression of apelin signaling linked to various protein kinases. Pharmacokinetic and toxicity assessments confirm the specificity, safety, and stability of apelin-dm, as well as its facile hepatic metabolism. These findings position targeting proapelin cleavage as a promising therapeutic strategy against metastatic colorectal cancer, paving the way for further clinical exploration.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"504-534"},"PeriodicalIF":9.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440089","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}

{"title":"Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke.","authors":"Fuqi Mei, Deyu Deng, Zijun Cao, Liyan Lou, Kangmin Chen, Minjie Hu, Zhenhu Zhu, Jiangyun Shen, Jianzhao Zhang, Jie Liang, Jingyong Huang, Min Bao, Ari Waisman, Xu Wang","doi":"10.1038/s44321-025-00206-6","DOIUrl":"https://doi.org/10.1038/s44321-025-00206-6","url":null,"abstract":"<p><p>As a common and severe cerebrovascular disease, ischemic stroke casts a significant shadow over global health. Unfortunately, the mechanisms regulating neuronal death in the affected areas remain largely unclear. Here, we found that deletion of the deubiquitinating enzyme Otubain-2 (OTUB2) significantly alleviated ischemia-induced cerebral infarction and neurological deficits, accompanied by a reduction in neuronal loss, glial activation, and neuroinflammation. OTUB2 was predominantly expressed in neurons and its deletion decreased receptor-interacting protein kinase 3 (RIPK3)-mediated neuronal necroptosis. Moreover, OTUB2 increased RIPK3 protein abundance by inhibiting the proteasomal degradation of RIPK3. Mechanistically, OTUB2 removed K48-linked polyubiquitin chains from RIPK3 through its active site C51. Importantly, pharmacological inhibition of OTUB2 alleviated ischemic brain injury in mice and reduced oxygen-glucose deprivation-induced neuronal death in human brain organoids. These results demonstrate that OTUB2 critically regulates ischemic stroke injury by potentiating neuronal necroptosis, suggesting that OTUB2 inhibition may become a potential therapeutic approach for treating ischemic stroke.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safe CAR-T: shedding light on CAR-related T-cell malignancies.","authors":"Qibin Liao, Jianqing Xu","doi":"10.1038/s44321-025-00205-7","DOIUrl":"https://doi.org/10.1038/s44321-025-00205-7","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"X-linked myopathy with excessive autophagy: characterization and therapy testing in a zebrafish model.","authors":"Lily Huang, Rebecca Simonian, Michael A Lopez, Muthukumar Karuppasamy, Veronica M Sanders, Katherine G English, Lacramioara Fabian, Matthew S Alexander, James J Dowling","doi":"10.1038/s44321-025-00204-8","DOIUrl":"10.1038/s44321-025-00204-8","url":null,"abstract":"<p><p>X-linked myopathy with excessive autophagy (XMEA), a rare childhood-onset autophagic vacuolar myopathy caused by mutations in VMA21, is characterized by proximal muscle weakness and progressive vacuolation. VMA21 encodes a protein chaperone of the vacuolar hydrogen ion ATPase, the loss of which leads to lysosomal neutralization and impaired function. At present, there is an incomplete understanding of XMEA, its mechanisms, consequences on other systems, and therapeutic strategies. A significant barrier to advancing knowledge and treatments is the lack of XMEA animal models. Therefore, we used CRISPR-Cas9 editing to engineer a loss-of-function mutation in zebrafish vma21. The vma21 mutant zebrafish phenocopy the human disease with impaired motor function and survival, liver dysfunction, and dysregulated autophagy indicated by lysosomal de-acidification, the presence of characteristic autophagic vacuoles in muscle fibers, altered autophagic flux, and reduced lysosomal marker staining. As proof-of-concept, we found that two drugs, edaravone and LY294002, improve swim behavior and survival. In total, we generated and characterized a novel preclinical zebrafish XMEA model and demonstrated its suitability for studying disease pathomechanisms and identifying potential therapeutic targets.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pertussis before, during and after Covid-19.","authors":"Camille Locht","doi":"10.1038/s44321-025-00199-2","DOIUrl":"https://doi.org/10.1038/s44321-025-00199-2","url":null,"abstract":"<p><p>After the Covid-19 pandemic, pertussis has made a spectacular comeback in Europe and many other parts of the world, while during the pandemic it had essentially disappeared because of the social distancing requirements. However, even before the Covid-19 pandemic, the disease was on the rise in many countries, especially those that have replaced whole-cell pertussis vaccines by acellular pertussis vaccines. Several reasons may account for this upsurge, including strain adaptation to escape vaccine-induced immunity, rapid waning of immunity after vaccination and the failure of current vaccines to prevent infection by and transmission of the causative agent Bordetella pertussis. Various strategies have been deployed to control the disease, the most effective of which is maternal vaccination during pregnancy to protect the newborn against the most severe and deadly forms of the disease. However, ultimate control of pertussis likely requires novel vaccines, which prevent infection and transmission, not only disease. One of them is the live attenuated BPZE1 vaccine, which has shown promise in pre-clinical and clinical studies and may therefore perhaps become a gamechanger.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy.","authors":"Nozomi Tomimatsu, Luis Fernando Macedo Di Cristofaro, Suman Kanji, Lorena Samentar, Benjamin Russell Jordan, Ralf Kittler, Amyn A Habib, Jair Machado Espindola-Netto, Tamara Tchkonia, James L Kirkland, Terry C Burns, Jann N Sarkaria, Andrea Gilbert, John R Floyd, Robert Hromas, Weixing Zhao, Daohong Zhou, Patrick Sung, Bipasha Mukherjee, Sandeep Burma","doi":"10.1038/s44321-025-00201-x","DOIUrl":"https://doi.org/10.1038/s44321-025-00201-x","url":null,"abstract":"<p><p>Glioblastomas (GBM) are routinely treated with high doses of ionizing radiation (IR), yet these tumors recur quickly, and the recurrent tumors are highly therapy resistant. Here, we report that IR-induced senescence of tumor cells counterintuitively spurs GBM recurrence, driven by the senescence-associated secretory phenotype (SASP). We find that irradiated GBM cell lines and patient derived xenograft (PDX) cultures senesce rapidly in a p21-dependent manner. Senescent glioma cells upregulate SASP genes and secrete a panoply of SASP factors, prominently interleukin IL-6, an activator of the JAK-STAT3 pathway. These SASP factors collectively activate the JAK-STAT3 and NF-κB pathways in non-senescent GBM cells, thereby promoting tumor cell proliferation and SASP spreading. Transcriptomic analyses of irradiated GBM cells and the TCGA database reveal that the cellular inhibitor of apoptosis protein 2 (cIAP2), encoded by the BIRC3 gene, is a potential survival factor for senescent glioma cells. Senescent GBM cells not only upregulate BIRC3 but also induce BIRC3 expression and promote radioresistance in non-senescent tumor cells. We find that second mitochondria-derived activator of caspases (SMAC) mimetics targeting cIAP2 act as novel senolytics that trigger apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells. Finally, using both PDX and immunocompetent mouse models of GBM, we show that the SMAC mimetic birinapant, administered as an adjuvant after radiotherapy, can eliminate senescent GBM cells and prevent the emergence of recurrent tumors. Taken together, our results clearly indicate that significant improvement in GBM patient survival may become possible in the clinic by eliminating senescent cells arising after radiotherapy.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Female sex is linked to a stronger association between sTREM2 and CSF p-tau in Alzheimer's disease.","authors":"Davina Biel, Marc Suárez-Calvet, Anna Dewenter, Anna Steward, Sebastian N Roemer, Amir Dehsarvi, Zeyu Zhu, Julia Pescoller, Lukas Frontzkowski, Annika Kreuzer, Christian Haass, Michael Schöll, Matthias Brendel, Nicolai Franzmeier","doi":"10.1038/s44321-024-00190-3","DOIUrl":"10.1038/s44321-024-00190-3","url":null,"abstract":"<p><p>In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau₁₈₁ determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau₁₈₁. To determine effects of microglial activation on p-tau₁₈₁, we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher Aβ-related p-tau₁₈₁ levels. Higher sTREM2 was associated with elevated p-tau₁₈₁, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau₁₈₁ levels and faster p-tau₁₈₁ increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"235-248"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964253","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}

{"title":"PlexinD1 is a driver and a therapeutic target in advanced prostate cancer.","authors":"Jing Wei, Jing Wang, Wen Guan, Jingjing Li, Tianjie Pu, Eva Corey, Tzu-Ping Lin, Allen C Gao, Boyang Jason Wu","doi":"10.1038/s44321-024-00186-z","DOIUrl":"10.1038/s44321-024-00186-z","url":null,"abstract":"<p><p>Aggressive prostate cancer (PCa) variants associated with androgen receptor signaling inhibitor (ARSI) resistance and metastasis remain poorly understood. Here, we identify the axon guidance semaphorin receptor PlexinD1 as a crucial driver of cancer aggressiveness in metastatic castration-resistant prostate cancer (CRPC). High PlexinD1 expression in human PCa is correlated with adverse clinical outcomes. PlexinD1 critically maintains CRPC aggressive behaviors in vitro and in vivo, and confers stemness and cellular plasticity to promote multilineage differentiation including a neuroendocrine-like phenotype for ARSI resistance. Mechanistically, PlexinD1 is upregulated upon relief of AR-mediated transcriptional repression of PlexinD1 under ARSI treatment, and subsdquently transactivates ErbB3 and cMet via direct interaction, which triggers the ERK/AKT pathways to induce noncanonical Gli1-dictated Hedgehog signaling, facilitating the growth and plasticity of PCa cells. Blockade of PlexinD1 by the protein inhibitor D1SP restricted CRPC growth in multiple preclinical models. Collectively, these findings characterize PlexinD1's contribution to PCa progression and offer a potential PlexinD1-targeted therapy for advanced PCa.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"336-364"},"PeriodicalIF":9.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920817","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}