Clinical and Translational Medicine最新文献

{"title":"Clinical implement of Probe-Capture Metagenomics in sepsis patients: A multicentre and prospective study","authors":"Qin Sun, Ran Teng, Qiankun Shi, Yun Liu, Xing Cai, Bin Yang, Quan Cao, Chang Shu, Xu Mei, Weiqi Zeng, Bingxue Hu, Junyi Zhang, Haibo Qiu, Ling Liu","doi":"10.1002/ctm2.70297","DOIUrl":"https://doi.org/10.1002/ctm2.70297","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Accurate pathogen identification is critical for managing sepsis. However, traditional microbiological methods are time-consuming and exhibit limited sensitivity, particularly with blood samples. Metagenomic sequencing of plasma or whole blood was highly affected by the proportion of host nucleic acid.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We developed a Probe-Capture Metagenomic assay and established a multicentre prospective cohort to assess its clinical utility. In this study, 184 blood samples from patients suspected of sepsis were sent for blood culture and Probe-Capture Metagenomic sequencing before using antibiotics. The pathogen-positive rate and auxiliary abilities in diagnosis were compared among Probe-Capture Metagenomics, blood culture and real-time PCR (RT-PCR). Antibiotic therapy adjustments were based on the identification of pathogens, and changes in the Sequential Organ Failure Assessment (SOFA) score were monitored on days 0, 3 and 7 of admission.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 184 sepsis patients were enrolled, with a mean age of 66 years (range 56–74). The Probe-Capture Metagenomics method, confirmed by RT-PCR, demonstrated a significantly higher pathogen detection rate than blood culture alone (51.6% vs. 17.4%, <i>p</i> < .001). When combining the results of blood culture and RT-PCR, Probe-Capture Metagenomics achieved a concordance rate of 91.8% (169/184), with a sensitivity of 100% and specificity of 87.1%. In terms of clinical impact, antibiotic therapy was adjusted for 64 patients (34.8%) based on the results from Probe-Capture Metagenomics, and 41 patients (22.3%) showed a > 2-point decrease in SOFA score following antibiotic adjustments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Probe-Capture Metagenomics significantly enhances the ability of pathogen detection compared with traditional metagenomics. Compared to blood culture and RT-PCR in sepsis patients, it leads to improved antibiotic treatment and better patient outcomes. This study, for the first time, evaluates the clinical impact of metagenomic sequencing by integrating antibiotic adjustments and SOFA score changes, indicating that approximately one-fifth of sepsis patients benefit from this advanced diagnostic approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial registration</h3>\u0000 \u0000 <p>This study has been registered in clinical trials (clinicaltrials.gov) on 30 November 2018, and the regi","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770400","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":"Targeting biomolecular condensates to inhibit breast cancer","authors":"Xiaoxue Zhou, Linghui Zeng, Fangfang Zhou","doi":"10.1002/ctm2.70296","DOIUrl":"https://doi.org/10.1002/ctm2.70296","url":null,"abstract":"<p>Breast cancer remains one of the most prevalent and deadly cancers worldwide, with metastasis being the primary cause of mortality.<span><sup>1</sup></span> Despite significant advances in treatment, the development of resistance to conventional therapies and the lack of effective strategies to prevent metastasis continue to pose major challenges.<span><sup>2</sup></span> One of the most exciting developments in cancer biology in recent years has been the discovery of liquid–liquid phase separation (LLPS), a process by which proteins and other biomolecules form membraneless organelles or condensates within cells.<span><sup>3</sup></span> These condensates compartmentalise biochemical reactions, allowing for the regulation of complex cellular processes, including transcription, DNA repair, and signal transduction.<span><sup>4-6</sup></span> In the context of cancer, LLPS has been implicated in the dysregulation of key oncogenic pathways.<span><sup>7, 8</sup></span> The aberrant formation and regulation of phase-separated condensates are increasingly recognised as critical factors driving tumourigenesis and metastasis.<span><sup>9</sup></span> However, targeting these condensates for therapeutic intervention remains a significant challenge.</p><p>In this context, the recent discovery of the role of FOXM1 (Forkhead box protein M1) in breast cancer progression, and the development of a novel therapeutic strategy to target its phase-separated condensates, represents a groundbreaking advancement with profound implications for clinicians and clinical researchers.<span><sup>10</sup></span> In our recent study, we identified FOXM1 as a protein that undergoes LLPS in breast cancer cells.<span><sup>10</sup></span> FOXM1 condensates form in the nucleus, where they compartmentalise the transcription machinery, maintaining chromatin accessibility and super-enhancer landscapes that are crucial for tumour growth and metastasis. FOXM1 is a transcription factor that plays a critical role in cell cycle progression, DNA repair, and cellular differentiation. It is frequently overexpressed in various cancers, including breast cancer, where it drives tumour growth, metastasis, and resistance to therapy. This phase-separated state of FOXM1 enhances its transcriptional activity, driving the expression of oncogenic genes that promote tumour progression (Figure 1A).</p><p>A key finding of our research is that the formation of FOXM1 condensates can be disrupted by the activation of AMP-activated protein kinase (AMPK), a cellular energy sensor that plays a critical role in maintaining metabolic homeostasis. We discovered that AMPK phosphorylates FOXM1 at a specific site Ser376 within its intrinsically disordered region (IDR), leading to the dissolution of FOXM1 condensates. This phosphorylation event introduces electrostatic repulsion, preventing FOXM1 from undergoing LLPS and aggregating into functional condensates. The disruption of FOXM1 condensates by AMPK activation ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749290","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":"Towards a unified framework for single-cell -omics-based disease prediction through AI","authors":"Matteo Barberis,&nbsp;Jinkun Xie","doi":"10.1002/ctm2.70290","DOIUrl":"https://doi.org/10.1002/ctm2.70290","url":null,"abstract":"<p>Single-cell omics has emerged as a powerful tool for elucidating cellular heterogeneity in health and disease. Parallel advances in artificial intelligence (AI), particularly in pattern recognition, feature extraction and predictive modelling, now offer unprecedented opportunities to translate these insights into clinical applications. Here, we propose single-cell -omics-based Disease Predictor through AI (scDisPreAI), a unified framework that leverages AI to integrate single-cell -omics data, enabling robust disease and disease-stage prediction, alongside biomarker discovery. The foundation of scDisPreAI lies in assembling a large, standardised database spanning diverse diseases and multiple disease stages. Rigorous data preprocessing, including normalisation and batch effect correction, ensures that biological rather than technical variation drives downstream models. Machine learning pipelines or deep learning architectures can then be trained in a multi-task fashion, classifying both disease identity and disease stage. Crucially, interpretability techniques such as SHapley Additive exPlanations (SHAP) values or attention weights pinpoint the genes most influential for these predictions, highlighting biomarkers that may be shared across diseases or disease stages. By consolidating predictive modelling with interpretable biomarker identification, scDisPreAI may be deployed as a clinical decision assistant, flagging potential therapeutic targets for drug repurposing and guiding tailored treatments. In this editorial, we propose the technical and methodological roadmap for scDisPreAI and emphasises future directions, including the incorporation of multi-omics, standardised protocols and prospective clinical validation, to fully harness the transformative potential of single-cell AI in precision medicine.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70290","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749288","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":"Erratum for the Clinical and Translational Medicine “Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING signalling” by Zijuan Wu et al.","authors":"Zijuan Wu,&nbsp;Wei Zhang,&nbsp;Luqiao Wang,&nbsp;Jiayan Leng,&nbsp;Yongle Li,&nbsp;Zhou Fan,&nbsp;Mengtao Zhan,&nbsp;Lei Cao,&nbsp;Yongning Jiang,&nbsp;Yan Jiang,&nbsp;Bing Sun,&nbsp;Jianxin Fu,&nbsp;Jianyong Li,&nbsp;Wenyu Shi,&nbsp;Hui Jin","doi":"10.1002/ctm2.70301","DOIUrl":"https://doi.org/10.1002/ctm2.70301","url":null,"abstract":"<p>Zijuan Wu. Clin Transl Med. 2024;14(8):e1807.</p><p>Following the publication of the original article,<span>¹</span> the authors identified minor errors in Figure 1C, where the images of one group was incorrect. Because during the image acquisition, we mistakenly labelled two duplicate results from a single sample. We have made the necessary corrections to Figure 1C. More importantly, we promise that the erratum has no impact on the conclusion and description of the article.</p><p>We apologize for this error.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749289","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":"Transitional CXCL14+ cancer-associated fibroblasts enhance tumour metastasis and confer resistance to EGFR-TKIs, revealing therapeutic vulnerability to filgotinib in lung adenocarcinoma","authors":"Weijiao Xu,&nbsp;Haitang Yang,&nbsp;Ke Xu,&nbsp;Anshun Zhu,&nbsp;Sean R. R. Hall,&nbsp;Yunxuan Jia,&nbsp;Baicheng Zhao,&nbsp;Enshuo Zhang,&nbsp;Gang Liu,&nbsp;Jianlin Xu,&nbsp;Thomas M. Marti,&nbsp;Ren-Wang Peng,&nbsp;Patrick Dorn,&nbsp;Yongliang Niu,&nbsp;Xufeng Pan,&nbsp;Yajuan Zhang,&nbsp;Feng Yao","doi":"10.1002/ctm2.70281","DOIUrl":"https://doi.org/10.1002/ctm2.70281","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The heterogeneity of cancer-associated fibroblasts (CAFs) has become a crucial focus in understanding cancer biology and treatment response, revealing distinct subpopulations with specific roles in tumor pathobiology. CAFs have also been shown to promote resistance in lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the specific CAF subsets responsible for driving tumor advancement and resistance to EGFR-TKIs in lung adenocarcinoma (LUAD) remain poorly understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We integrate multiple scRNA-seq datasets to identify cell subclusters most relevant to tumor stage, patient survival, and EGFR–TKIs response. Additionally, in vitro and in vivo experiments, clinical tissue sample immunohistochemistry and patient plasma ELISA experiments are performed to validate key findings in independent LUAD cohorts.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;By analyzing multiple scRNA-seq and spatial transcriptomic datasets, we identified a unique subset of CXCL14+ myofibroblastic CAFs (myCAFs), emerging during the early differentiation phase of pan-cancer invasiveness-associated THBS2⁺ POSTN⁺ COL11A1⁺ myCAFs. Notably, plasma levels of CXCL14 in LUAD patients correlate significantly with tumor stage. Mechanistically, this subset enhances tumor aggressiveness through epithelial-to-mesenchymal transition and angiogenesis. Among standard treatment regimens, transitional CXCL14+ myCAFs specifically confer resistance to EGFR-TKIs, while showing no significant impact on chemotherapy or immunotherapy outcomes. Through a pharmacological screen of FDA-approved drugs, we identified Filgotinib as an effective agent to counteract the EGFR-TKIs resistance conferred by this CAF subset.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In summary, our study highlights the role of the differentiated stage from transitional CXCL14+ myCAFs to invasiveness-associated myCAFs in driving tumor progression and therapy resistance in LUAD, positioning Filgotinib as a promising targeted therapy for this process. These insights may enhance patient stratification and inform precision treatment strategies in LUAD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Single-cell analysis identifies transitional CXCL14&lt;sup&gt;+&lt;/sup&gt; myofibroblastic cancer-associated fibroblasts (myCAFs) pred","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741485","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":"A myeloid IFN gamma response gene signature correlates with cancer prognosis","authors":"Yuchao Zhang,&nbsp;Asma Khanniche,&nbsp;Yizhe Li,&nbsp;Zhenchuan Wu,&nbsp;Hailong Wang,&nbsp;Hongyu Zhang,&nbsp;Xiaoxue Li,&nbsp;Landian Hu,&nbsp;Xiangyin Kong","doi":"10.1002/ctm2.70139","DOIUrl":"https://doi.org/10.1002/ctm2.70139","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The IFN-γ cytokine plays a dual role in anti-tumor immunity, enhancing immune defense against cancer cells while promoting tumor survival and progression. Its influence on prognosis and therapeutic responses across cancer types remains unclear.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study aimed to perform a pan-cancer analysis of IFN-γ response genes to determine their prognostic significance and evaluate their impact on clinical outcomes and anti-PD1 immunotherapy responses.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Using multiple datasets, 46 IFN-γ response genes were identified as prognostic for disease-specific survival, and their expression was used to construct the IFN-γ Response Gene Network Signature (IFGRNS) score. The prognostic and therapeutic relevance of the IFGRNS score was assessed across cancer types, considering tumor pathology, genomic alterations, tumor mutation burden, and microenvironment. Single-cell transcriptomic analysis identified cellular contributors, and a murine pancreatic cancer (PAN02) model was used to validate findings with anti-PD1 therapy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The IFGRNS score emerged as a robust prognostic indicator of survival, with higher scores correlating with worse outcomes in most cancer types. The prognostic significance of the score was influenced by factors such as cancer type, tumor pathology, and the tumor microenvironment. Single-cell analysis revealed that myeloid cells, particularly the M2 macrophage subtype, demonstrated high levels of IFGRNS expression, which was associated with tumor progression. A negative correlation was observed between the IFGRNS score and outcomes to anti-PD1 immunotherapy in urologic cancers, where patients with higher scores showed worse prognosis and lower response rates to therapy. Experimental validation in the PAN02 murine model confirmed that anti-PD1 therapy significantly reduced tumor size and IFGRNS expression in M2 macrophages, supporting the clinical findings.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The IFGRNS score is a novel prognostic indicator for survival and therapeutic responses in cancer. These findings underline the complexity of IFN-γ signaling and suggest potential applications for the IFGRNS score in cancer diagnosis, prognosis, and immunotherapy.&lt;/p&gt;\u0000 \u0000 &lt;p&gt;&lt;b&gt;Novelty &amp; impact statements&lt;/b&gt;: IFN-γ response genes play a signifi","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741658","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":"The FBP1-TP53-NRF2 metabolic switch in metabolic dysfunction-associated steatohepatitis-hepatocellular carcinoma progression and senescence reversal","authors":"Yahui Zhu,&nbsp;Donglin Wei,&nbsp;Michael Karin,&nbsp;Li Gu","doi":"10.1002/ctm2.70293","DOIUrl":"https://doi.org/10.1002/ctm2.70293","url":null,"abstract":"&lt;p&gt;Metabolic dysfunction-associated steatohepatitis (MASH) is defined by extensive hepatosteatosis, liver injury, persistent inflammation and fibrosis.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Around 2% of patients with MASH progress to MASH-related hepatocellular carcinoma (MASH-HCC) every year, indicating the importance of MASH as the newly emerging HCC aetiology.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Nonetheless, it is not understood how MASH progresses to HCC and how MASH is maintained in some patients without progression to HCC. Here, we outline our recently discovered mechanism by which energy-dense diets induce hepatocyte senescence, previously presumed to prevent HCC progression. Using fructose and fat-rich diets we found diet-induced hepatocyte single-strand DNA breaks that lead to activation of the DNA damage response (DDR), which culminates in the activation of TP53 and induction of its targets p21&lt;sup&gt;CIP1&lt;/sup&gt; and p16&lt;sup&gt;INK4a&lt;/sup&gt;, two cell-cycle inhibitors that enter DNA damaged hepatocytes into senescence, a state during which they cannot proliferate. Interestingly, we found that TP53 also leads to the induction of the metabolic enzyme FBP1, which we previously identified as an AKT inhibitor due to its ability to interact with both AKT and PP2A catalytic subunit, which inactivates AKT.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; By inhibiting AKT, FBP1 which also acts as an HCC-specific tumour suppressor,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; leads to stabilization of TP53, thereby boosting hepatocyte senescence&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; (Figure 1). FBP1 is upregulated during MASH, but as MASH progresses to HCC FBP1 is degraded and leads to activation of AKT, in insulin and growth factor-stimulated hepatocytes. By phosphorylating MDM2 and enhancing its ability to induce TP53 degradation,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; the downregulation of FBP1 also leads to TP53 deficiency, thereby allowing senescent hepatocytes to re-enter the cell cycle. Conversely, the upregulation of FBP1 in response to energy-dense and DNA-damaging diets inhibits the phosphorylation of GSK3α/β, thereby increasing the substrate binding activity of these kinases which phosphorylate NRF2 and β-catenin and thereby triggering their degradation, resulting in low NRF2 expression in senescent hepatocytes.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, sustained metabolic stress and autophagy disruption lead to accumulation of p62/SQSTM1 which sequesters the major negative regulator of NRF2, KEAP1. This results in NRF2 activation, which induces the expression of ERK1/2-activating EGF and PDGF family members and phosphorylation-directed and TRIM28-dependent FBP1 degradation (Figure 1). FBP1 degradation, as discussed above, also results in TP53 degradation.&lt;/p&gt;&lt;p&gt;On the one hand, after oncogene activation, senescence-induced immune surveillance by CD8&lt;sup&gt;+&lt;/sup&gt; T cells clears premalignant cells and inhibits liver tumorigenesis.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; However, MASH is associated with liver fibrosis driven by transforming growth factor-β, whic","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741212","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":"GDF-15 blockade: A multi-directional approach to potentiate cancer immunotherapy and alleviate cancer cachexia","authors":"Ignacio Melero,&nbsp;Kathrin Klar,&nbsp;Eugen Leo","doi":"10.1002/ctm2.70280","DOIUrl":"https://doi.org/10.1002/ctm2.70280","url":null,"abstract":"<p>Metastatic solid tumours remain a major challenge in clinical medicine, demanding innovation with novel treatment approaches and new synergistic combinations. Immunotherapy with immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 has improved the treatment outcome for numerous tumour types in a groundbreaking way. However, resistance to immunotherapy is very frequent and ultimately impacts the vast majority of patients treated, often resulting in fatal outcome. Similarly, in advanced cancer patients cachexia is a frequent event. This is a serious debilitating syndrome characterized by severe muscle wasting, weight loss and systemic metabolic dysfunction which associates with a dismal prognosis. Cachexia further worsens clinical outcome in cancer patients and can prevent ability to continue on therapy. In this context, our recent study published in Nature, titled “Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours,” demonstrates the multifaceted roles growth differentiation factor 15 (GDF-15) plays and provides initial data on a promising novel therapeutic strategy to counteract immunotherapy resistance and cachexia.<span>¹</span> Here, we discuss the potential benefits of GDF-15 blockade as an emerging approach to both potentiate cancer immunotherapy and simultaneously mitigate cancer cachexia, highlighting recent advancements and their potential future clinical implications (Figure 1).</p><p>I. Melero, K. Klar and E. Leo prepared jointly the manuscript.</p><p>I. Melero is principal investigator of the trial 1 and has served as a consultant to Catalym GmbH. K. Klar and E. Leo are employees of Catalym GmbH, Martinsried, Germany, a biotechnology company developing the anti-GDF15 antibody visugromab.</p><p>The authors declare human ethics approval does not apply for this manuscript.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70280","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741591","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":"The role of metabolite sensors in metabolism-immune interaction: New targets for immune modulation","authors":"Qiqing Yang,&nbsp;Ce Guo,&nbsp;Long Zhang","doi":"10.1002/ctm2.70294","DOIUrl":"https://doi.org/10.1002/ctm2.70294","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Recent advancements in immunometabolism have highlighted the critical role of metabolite sensors in regulating immune responses. Metabolites such as lactate, succinate, itaconate, and β-hydroxybutyrate influence immune cell function by interacting with specific sensors. These metabolites act as signaling molecules, linking cellular metabolic changes to immune responses. Lactate, a metabolite commonly produced under hypoxic conditions, has emerged as a major regulator of innate immunity. Key enzymes, including AARS1 and AARS2, function as intracellular lactate sensors, catalyzing lactylation on proteins like cGAS, which plays a central role in DNA sensing and immune activation. The lactylation of cGAS inhibits its activity, modulating immune responses by balancing inflammation and immune tolerance. Metabolite sensors, like MCT1, also contribute to immune modulation, particularly in cancer and chronic inflammatory diseases. Therapeutically, targeting these sensors offers potential for restoring immune function, especially in cancer immunotherapy. However, challenges in specificity, off-target effects, and long-term safety require further investigation. This article explores the emerging role of metabolite sensors in immune regulation, with a focus on lactate sensors, and outlines potential therapeutic strategies to enhance immune responses in metabolic diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70294","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741592","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":"BORA overexpression promotes epithelial–mesenchymal transition and metastasis in ovarian cancer: Unveiling a novel therapeutic target for advanced disease","authors":"Marta Barber,&nbsp;Ariadna Boloix,&nbsp;Alfonso Parrilla,&nbsp;Mariana Köber,&nbsp;Laia Avilés-Domínguez,&nbsp;Nora Ventosa,&nbsp;Lidia del Carmen Ramírez-Morales,&nbsp;Asunción Perez-Benavente,&nbsp;Antonio Gil-Moreno,&nbsp;Eva Colàs,&nbsp;Juan Morote,&nbsp;Miguel F. Segura,&nbsp;Olga Méndez,&nbsp;Anna Santamaria","doi":"10.1002/ctm2.70285","DOIUrl":"https://doi.org/10.1002/ctm2.70285","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;We are pleased to present our latest findings, which demonstrate that BORA plays a key role in the metastatic capacity of ovarian cancer (OC) cells by triggering a PLK1-mediated induction of epithelial-mesenchymal transition (EMT). Additionally, our research suggests that the inhibition of BORA could offer a novel strategy for improving OC prognosis.&lt;/p&gt;&lt;p&gt;OC is the most lethal gynaecologic malignancy given that most patients are diagnosed at advanced stages, when the disease has already metastasized, and the 5-year survival rate is below 30%.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The most common and aggressive subtype is high-grade serous carcinoma (HGSC), which is a highly heterogeneous tumour generally chemoresistant.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Polo-like kinase 1 (PLK1), a master regulator of mitosis,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; is responsible for triggering EMT in various cancers by activating multiple signalling pathways (Figure S1).&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Although several PLK1 inhibitors have been developed, their antitumour activity against solid tumours is modest, primarily due to poor selectivity and toxicity arising from targeting other PLK family members.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; Notably, BORA, a specific cofactor of PLK1, has emerged as a potential target for selectively blocking PLK1 activity. BORA activates PLK1 by binding it, causing a conformational change that enables Aurora A to phosphorylate PLK1 at T210, initiating mitotic entry.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; We propose that BORA not only activates PLK1 to trigger mitosis but also to induce EMT.&lt;/p&gt;&lt;p&gt;Previous results from our group demonstrated that BORA expression is higher in OC metastatic samples than in paired primary tumours.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; In the present study, we confirmed that BORA mRNA expression (GSE73168) was higher in ascitic fluid-derived OC cells than in the matched primary tumours (Figure S2). Transcriptomic analyses were performed to elucidate BORA mechanism of action. In vivo overexpression of BORA (BORA_OE) in SKOV3 OC xenografts led to an enrichment of genes associated with EMT and migration (Figure 1A,B). Significantly upregulated genes included the main mesenchymal marker N-cadherin (&lt;i&gt;CDH2&lt;/i&gt;) and several matrix metalloproteases (e.g., &lt;i&gt;MMP13&lt;/i&gt;) (Figure 1B). The correlation between BORA mRNA expression and the expression of several metastasis-associated genes was validated in the ovarian serous cystadenocarcinoma TCGA cohort (2022-v32) (Figure S3D–G).&lt;/p&gt;&lt;p&gt;To confirm whether the gene expression deregulation produced by BORA_OE generated a mesenchymal phenotype, we compared BORA_OE cells with control cells treated with TGFβ, a well-known EMT inducer. Our results showed that, under both conditions, the mRNA levels of the mesenchymal markers ZEB1, SNAI2, MMP13, and LAMA1 were markedly increased, whereas the expression of the epithelial marker CDH1 was reduced (Figure 1C). At the protein level, BORA_OE increased the levels of N-","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70285","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717032","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}