Clinical and Translational Medicine最新文献

{"title":"Comparative spatial transcriptomics of pancreatic cancer with ductal and acinar origins in mouse models","authors":"Ming Cui, Jialu Bai, Xiaoyan Chang, Ruiling Xiao, Shengwei Mo, Kevin C Soares, Sen Yang, Lei You, Quan Liao, Jin He, Ya Hu, Yupei Zhao","doi":"10.1002/ctm2.70416","DOIUrl":"https://doi.org/10.1002/ctm2.70416","url":null,"abstract":"<p>Dear Editor,</p><p>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, and while both acinar and ductal cells can contribute to its origin, their roles in defining PDAC subtypes remain unclear.<span><sup>1</sup></span> Investigating the cellular origin of PDAC may provide valuable insights into the biological processes of carcinogenesis and inform novel clinical classification schemes, enabling more precise and effective diagnostic and therapeutic strategies. Acinar cell-derived PDAC, often through acinar-to-ductal metaplasia (ADM), has been well-studied using models such as <i>Pdx1-Cre</i> or <i>Ptf1a-Cre</i>.<span><sup>2-4</sup></span> Ductal cells can also give rise to precursor lesions, including intraductal papillary mucinous neoplasms (IPMN), which is an imaging-recognizable lesion that is helpful for the early diagnosis of PDAC.<span><sup>5</sup></span> However, models focusing on ductal cell-derived PDAC remain limited. Transcription factor Sox9, a hallmark marker of pancreatic ductal cells, enables lineage-specific gene editing via <i>Sox9-CreER</i>.<span><sup>6, 7</sup></span> In this study, we induced the carcinogenesis of PDAC by conditionally activating <i>Kras<sup>G12D</sup></i> and deleting <i>Trp53</i> in ductal or acinar cells. Compared to the well-established KPPC (<i>Kras<sup>LSL-G12D/+</sup>;Trp53<sup>fl/fl</sup>;Pdx1-CreER</i>) mouse model, the KPPS (<i>Kras<sup>LSL-G12D/+</sup>;Trp53<sup>fl/fl</sup>;Sox9-CreER</i>) mouse model produces a substantial proportion of IPMN with varying pathological grades. Spatial transcriptomics further revealed partially shared, yet distinct, molecular and tumour microenvironment features between the KPPC and KPPS models, which were validated in human datasets.</p><p>We developed the KPPS mouse model and harvested pancreatic tissues between weeks 4 and 24 post-tamoxifen induction (Figure 1A,B and Figure S1A). H&E staining was performed on pancreatic formalin-fixed paraffin-embedded (FFPE) tissue sections from both KPPS and KPPC models (Figure 1C and Figure S1B). Histological analysis of tissues collected from KPPS mice revealed progressive development of IPMN, including low-grade (LG), high-grade (HG), and IPMN-associated invasive carcinoma (IPMN-IC), which exhibited characteristic tubular adenocarcinoma features (Histological criteria are elaborated in the supplementary information; Figure 1C,D). By 24 weeks post-Tamoxifen injection, all KPPS mice had progressed to invasive carcinoma, with IPMN-IC being the predominant phenotype, accounting for more than 80% of the cases, accompanied by conventional PDAC (Figure 1C, D). Immunohistochemical analysis of mucins (MUC) revealed that IPMN lesions from KPPS mice exhibited high expression of MUC1, weak expression of MUC5AC, and minimal to no expression of MUC2 (Figure 1E and Figure S1C), suggesting a non-intestinal IPMN subtype (including gastric and pancreatobiliary types). Notably, the IPMN-IC lesions predominantly exhibited featu","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70416","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714895","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":"Hijacking erythropoietin: A tumour-intrinsic strategy to escape immune surveillance","authors":"David Kung-Chun Chiu, Edgar G Engleman","doi":"10.1002/ctm2.70427","DOIUrl":"https://doi.org/10.1002/ctm2.70427","url":null,"abstract":"<p>An increasingly recognised framework in cancer immunology classifies tumours into T-cell-inflamed and non-inflamed phenotypes, based on the degree of immune cell infiltration, particularly cytotoxic CD8⁺ T cells.<span><sup>1</sup></span> Early studies demonstrated that CD8⁺ T-cell infiltration is one of the most informative immune features associated with a favourable prognosis.<span><sup>2</sup></span> Building on this insight, prognostic tools such as the Immunoscore were developed to quantify the density and spatial distribution of CD3⁺ and CD8⁺ T cells within the tumour core and invasive margin. This approach has shown that CD8⁺ T-cell infiltration can serve as a robust, immune-based classifier that outperforms traditional TNM staging in predicting clinical outcomes.<span><sup>3</sup></span> The introduction of immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis has transformed cancer therapy. However, response rates remain limited across many tumour types. One hypothesis is that effective responses to ICI require pre-existing anti-tumour T-cell immunity. Indeed, pioneering studies in melanoma demonstrated that patients with higher CD8⁺ T-cell densities at the invasive tumour margin were significantly more likely to respond to PD-1 blockade. Supporting this concept, a Phase II clinical trial in colorectal cancer showed that patients with a low Immunoscore did not benefit from PD-L1 blockade, whereas those with a high Immunoscore experienced a 65% reduction in disease progression risk.<span><sup>4</sup></span> These findings have led to the now widely accepted view that non-inflamed tumours are a major cause of resistance to ICI. This realisation has catalysed two central questions in the field: What determines whether a tumour is non-inflamed? And how can we reprogram non-inflamed tumours into an inflamed, immunologically active state?</p><p>To investigate these questions, our laboratory utilised a collection of autochthonous mouse models of hepatocellular carcinoma (HCC), each induced by different driver mutations and characterised by a defined T-cell-inflamed or non-inflamed immune phenotype.<span><sup>5</sup></span> Compared to conventional transplantable or cell line-based models, these autochthonous models more accurately recapitulate the complex features of human tumours, including their immune tumour microenvironment and responsiveness to ICI. Through direct comparison of T-cell-inflamed and non-inflamed HCC tumours, we identified that non-inflamed tumours exhibited significantly elevated levels of erythropoietin (EPO). Forced expression of EPO in the tumour cells of T-cell-inflamed tumours was sufficient to convert the tumours into a non-inflamed phenotype, marked by a significant reduction in CD8⁺ T-cell infiltration. Conversely, genetic ablation of EPO in non-inflamed tumours restored T-cell infiltration, effectively reprogramming the tumours into an inflamed, immune-responsive state. Mechanistically, we observed tha","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70427","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144714894","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 robust machine learning model based on ribosomal-subunit-derived piRNAs for diagnostic potential of nonsmall cell lung cancer across multicentre, large-scale of sequencing data","authors":"Zitong Gao,&nbsp;Masaki Nasu,&nbsp;Gehan Devendra,&nbsp;Ayman A. Abdul-Ghani,&nbsp;Anthony J. Herrera,&nbsp;Jeffrey A. Borgia,&nbsp;Christopher W. Seder,&nbsp;Donna Lee Kuehu,&nbsp;Zhuokun Feng,&nbsp;Yu Chen,&nbsp;Ting Gong,&nbsp;Zao Zhang,&nbsp;Owen Chan,&nbsp;Hua Yang,&nbsp;Jianhua Yu,&nbsp;Yuanyuan Fu,&nbsp;Lang Wu,&nbsp;Youping Deng","doi":"10.1002/ctm2.70418","DOIUrl":"https://doi.org/10.1002/ctm2.70418","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Nonsmall cell lung cancer (NSCLC) is a lethal cancer and lacks robust biomarkers for noninvasive clinical diagnosis. Detecting NSCLC at the early stage can decrease the mortality rate and minimise harm caused by various treatments. We curated 2050 samples from public tissue and plasma datasets including both invasive and noninvasive types, then supplemented with in-house pooled plasma and exosome samples. Eleven independent transcriptome datasets were utilised to develop a new machine learning model by integrating PIWI-interacting RNA (piRNA) to predict NSCLC. Five piRNA signatures derived from ribosomal subunits identified to be tumour-specific exhibited robust diagnostic ability and were combined into a piRNA-Based Tumour Probability Index (pi-TPI) risk evaluation model. pi-TPI effectively distinguished NSCLC patients from healthy individuals and showed efficacy in identifying early-stage cancers with Area under the ROC Curve (AUC) values over .80. Plasma cohorts exhibited the diagnosis efficacy of pi-TPI with an AUC value of .85. Experimental exosomal data enhances the accuracy of diagnosing noncancerous, benign, and cancer cases. The pi-TPI marker in the noncancer/cancer subgroup exhibited superior predictive performance with an AUC value of .96. These findings underscore the significant clinical potential of the five piRNA signatures as a powerful diagnostic tool for NSCLC, particularly of noninvasive cancer diagnostics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70418","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144705552","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":"Customised virus-like particles: Opening a new chapter for clinical precision gene therapy","authors":"Xingyu Zhu,&nbsp;Qingye Zhang,&nbsp;Xujiao Zhou,&nbsp;Yujia Cai,&nbsp;Jiaxu Hong","doi":"10.1002/ctm2.70395","DOIUrl":"https://doi.org/10.1002/ctm2.70395","url":null,"abstract":"&lt;p&gt;The CRISPR/Cas system, first discovered as an adaptive immune mechanism in bacteria and archaea, has evolved into a revolutionary technology capable of editing DNA loci and correcting genetic errors, offering new hope for the treatment of numerous hereditary and refractory diseases.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; This system employs a single-guide RNA (sgRNA) to direct the endonuclease Cas9 to a specific DNA target, where it generates double-strand breaks, thereby enabling site-specific modification.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In 2023, the US FDA approved the first gene therapy utilising CRISPR/Cas9 (Casgevy) for the treatment of sickle cell disease. This remarkable milestone has inspired researchers to continuously explore and push forward the clinical application of CRISPR-based therapies.&lt;/p&gt;&lt;p&gt;The safety and efficacy of gene therapy are two critical factors that must be prioritised when applying CRISPR in vivo.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Although several clinical trials – including those involving Casgevy – have demonstrated promising results, the long-term safety and efficacy remain to be fully observed. To achieve targeted and precise delivery of CRISPR components, various engineered carrier platforms have been developed, including nanomaterials, viral particles, and exosomes.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; Among these, virus-like particles (VLPs), owing to their transient expression, efficient delivery, and low immunogenicity, have emerged as a highly promising delivery modality.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; However, existing editing strategies based on VLPs have thus far failed to achieve cell-targeted gene editing in vivo.&lt;/p&gt;&lt;p&gt;To address this unmet need, a modular, targeted VLP platform named RIDE (RNP Integrating with Designer Envelope) was recently developed in our lab.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; RIDE enables cell-selective genome editing while preserving safety and transience.&lt;/p&gt;&lt;p&gt;A key strength of the RIDE platform lies in its dual modularity: the use of engineered VLPs to deliver Cas9 ribonucleoproteins (RNPs) and the incorporation of customisable envelope proteins for cell-specific targeting. Unlike conventional delivery systems that rely on passive diffusion or broad viral tropism, RIDE has been shown to be rationally redirected to virtually any cell type, either by adapting to the local tissue environment or by employing engineered ligands such as single-chain antibodies or DARPins. This flexibility represents a conceptual shift from broadly systemic, persistent delivery toward transient, tunable, and cell-selective genome editing – an essential step toward realising personalised and tissue-specific gene therapies.&lt;/p&gt;&lt;p&gt;Complementing its targeting versatility, RIDE also features a transient mode of action. Traditional vectors, such as adeno-associated viruses (AAVs) or lentiviruses (LVs), rely on DNA-based delivery, which can lead to prolonged Cas9 expression and increase the risk of off-target effects and genomic instability. In contrast","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70395","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695908","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":"","doi":"10.1002/ctm2.70312","DOIUrl":"https://doi.org/10.1002/ctm2.70312","url":null,"abstract":"<p>Following the publication of the original article,¹ the authors identified minor errors in Figure 1C, where the images of one group were 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 apologise for this error.</p><p>ORIGINAL FIGURE 1.</p><p></p><p>(C) AFM images of extracted eccDNAs in DLBCL cell lines. Scale bar, 200 nm.</p><p>UPDATED FIGURE 1.</p><p></p><p>(C) AFM images of extracted eccDNAs in DLBCL cell lines. Scale bar, 200 nm.</p><p>1. Wu Z, Zhang W, Wang L, et al. Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING signalling. <i>Clin Transl Med</i>. 2024;14(8):e1815 https://doi.org/10.1002/ctm2.1815.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695854","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":"Correction to “Inflammasome activation and metabolic remodeling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1”","authors":"","doi":"10.1002/ctm2.70379","DOIUrl":"https://doi.org/10.1002/ctm2.70379","url":null,"abstract":"<p>Gu X, Meng H, Peng C, et al. Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1. <i>Clin Transl Med</i>. 2023;13(6):1308.</p><p>In this article, the authors have just realized the wrong usages of immunoblotting bands for β-gal and p16 presented in Figure S1D and immunoblotting band for K48-polyubiquitin (Ub) presented in Figure S12K. The corrected Figures S1D and S12K are as follows. The quantitative analysis in Figure S1F has been conducted using this accurate immunoblotting result of Figures S1D.</p><p>The authors sincerely apologize for these errors. This correction does not affect the study's conclusions.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70379","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695907","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":"Early molecular changes predict cancer cachexia in LKB1-deleted mouse models of NSCLC","authors":"Gloriana Ndembe,&nbsp;Andrea David Re Cecconi,&nbsp;Federica Palo,&nbsp;Dorina Belotti,&nbsp;Laura Sala,&nbsp;Selena Foroni,&nbsp;Eugenio Scanziani,&nbsp;Rosanna Piccirillo,&nbsp;Massimo Broggini,&nbsp;Mirko Marabese","doi":"10.1002/ctm2.70360","DOIUrl":"https://doi.org/10.1002/ctm2.70360","url":null,"abstract":"<p>Dear Editor</p><p>This preclinical study highlights the potential for early cachexia assessment in LKB1-deficient non–small-cell lung cancer (NSCLC) by molecular analysis of multiple tissues. In addition, it opens new avenues for investigating the role of IL-12 as a protective factor against NSCLC-related cachexia.</p><p>To investigate the role of LKB1 in cancer-related cachexia, we used mouse cell lines derived from transgenic lung tumour nodules.<span>^{1, 2}</span> These cell lines, deleted in LKB1 but harbouring different Kirsten rat sarcoma virus (KRAS) mutations and the site of injection, were injected into immunocompetent mice. Regardless of the type of KRAS mutation, LKB1 deletion was associated with body weight loss (Figure S1).</p><p>To assess the possible role of sex,<span>³</span> we injected KRAS^G12D (K) and KRAS^G12D/LKB1^−/− (KL) NSCLC cells in male and female mice. K tumours grew faster than KL tumours in both sexes, with male mice facing faster overall tumour growth (Figures 1A and S2). Mice bearing KL tumour experienced rapid body weight loss, which was more pronounced in females. On day 26 post-inoculation, KL mice had significantly lower body weights than K or control mice, whereas K mice had body weights similar to those of the control mice (Figure 1B,C).</p><p>At sacrifice, KL mice showed statistically significant reductions in the gastrocnemius, tibialis anterior (TA) and soleus muscle weights. The extensor digitorum longus (EDL) muscle weight was significantly reduced only in females. Male K mice exhibited a significant reduction in gastrocnemius and TA muscle weights, while female K mice showed decreased soleus muscle weight (Figure 1D–G). Male KL mice also showed a severe reduction in visceral adipose tissue, which was completely absent in females. K tumours were associated with hepatosplenomegaly, whereas KL tumours were associated with liver mass reduction, especially in females (Figure 1H–J).</p><p>Histological analysis revealed hepatocellular atrophy, apoptosis, Kupffer cell hyperplasia and neutrophil infiltration in KL tumour-bearing mice (Figure S3). Food consumption remained unchanged before weight loss, but KL females showed reduced consumption at later stages. K mice showed no differences in food intake (Figure S4). Immunocompromised KL-bearing female mice also experienced weight loss, suggesting that the immune system is not the primary driver. In these animals also, K tumours grew faster than KL (Figure S5).</p><p>IL-6, a key mediator of cachexia,<span>⁴</span> was upregulated in KL cells compared to K cells in vitro (Figure 1K,L). In vivo, KL tumours showed higher IL-6 expression than K tumours, especially in males (Figure 1M). Liver IL-6 expression was elevated in both K and KL mice, with KL showing the highest levels (Figure 1N). IL-6 expression in the spleen differed by sex: in females, only KL tumours bearing mice showed IL-6 upregulation, wh","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687912","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":"Spatially resolved proteomics surveys the chemo-refractory proteins related to high-grade serous ovarian cancer","authors":"Linyuan Fan,&nbsp;Yi Liu,&nbsp;Haichao Zhou,&nbsp;Yang Feng,&nbsp;Guangyi Jiang,&nbsp;Guixue Hou,&nbsp;Zhihan Cao,&nbsp;Zhiguo Zheng,&nbsp;Lu Sun,&nbsp;Hao Chen,&nbsp;Yuefei Zhang,&nbsp;Weiran Chen,&nbsp;Yun Xi,&nbsp;Benliang Cheng,&nbsp;Qinghai Yang,&nbsp;Yan Ren,&nbsp;Jianqing Zhu,&nbsp;Siqi Liu","doi":"10.1002/ctm2.70422","DOIUrl":"https://doi.org/10.1002/ctm2.70422","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>High-grade serous ovarian carcinoma (HGSC) is a lethal malignancy characterized by high incidence, mortality, and chemoresistance. However, its molecular drivers are unknown. In this study, spatially resolved proteomics was applied to 1144 formalin-fixed paraffin-embedded tissue spots obtained by laser capture microdissection from 10 patients with HGSC and divergent carboplatin-paclitaxel (CP) responses. Specific sampling revealed stroma-driven tumour heterogeneity, identifying 642 tumour-specific and 180 stroma-specific proteins, with 505 CP-responsive therapeutic targets. Most of these protein signatures represented previously unreported associations with chemoresistance in HGSCs. Two clinically significant spatial proteomic maps were generated by introducing tumour (TS) and chemical (CS) scores. TS analysis revealed conserved tissue architecture across CP response groups, whereas CS mapping revealed pretreatment metabolic reprogramming (rather than proliferation) as the defining feature of chemo-resistant tumours, challenging current resistance paradigms. Immunohistochemical validation of HGSC tissue microarrays confirmed the spatial proteomic localization of TFRC and PDLIM3, which are linked to tumour progression, while establishing their novel role as chemotherapy resistance biomarkers through this study, with broader predictive potential observed across additional targets in the discovery cohort. This study developed a spatially resolved proteomic framework to enhance the diagnostic and therapeutic strategies for HGSC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>HGSC intra-tumour heterogeneity is predominantly driven by stroma, as revealed by spatial proteomic compartmentalization (tumour/stroma).</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Spatial proteomics expands the therapeutic target database, enabling prediction of platinum-based chemotherapy response.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Chemo-resistant patients exhibit pre-treatment metabolic activation rather than proliferative signatures.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>TFRC (iron transport) and PDLIM3 (cytoskeletal remodelling) are spatially validated as chemo-response biomarkers.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70422","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681607","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":"Precision treatment in breast cancer: Leveraging genetic interactions","authors":"Cai-Jin Lin,&nbsp;Xin Hu,&nbsp;Zhi-Ming Shao,&nbsp;Yi-Zhou Jiang","doi":"10.1002/ctm2.70407","DOIUrl":"https://doi.org/10.1002/ctm2.70407","url":null,"abstract":"&lt;p&gt;The advent of next-generation sequencing technology has catalyzed significant advancements in precision treatment strategies for breast cancer by leveraging insights into individual tumour genomes.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; This genome-guided approach has notably enhanced therapeutic outcomes, particularly in patients with specific genomic alterations (Figure 1).&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; For example, anti-HER2 targeted therapies exemplify a classical form of genotype-matched treatment specifically designed to target gene products in &lt;i&gt;ERBB2&lt;/i&gt;-amplified breast cancers.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; However, despite the initial success of precision treatment in breast cancer, clinical endeavours targeting individual alterations have yielded variable efficacy. One important reason is that clinical decision-making for precision treatment has overly focused on single driver alterations without considering potential interactions among multiple genomic alterations and their impact on efficacy.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The concept of genetic interactions, encompassing both the co-occurrence and mutual exclusivity of genomic alterations, highlights the complexity underlying breast cancer biology and treatment response.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Specifically, co-occurring genomic alterations can synergistically impact tumour behaviour and therapeutic responses (Figure 1). Targeting only one genomic alteration may lead to the development of drug resistance, whereas simultaneous targeting of both events has the potential to effectively eradicate the tumour. For instance, the presence of &lt;i&gt;PIK3CA&lt;/i&gt; co-mutations has been associated with poorer prognosis under anti-HER2 therapy.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; In addition, interactions such as &lt;i&gt;HER2-HER3&lt;/i&gt; co-alteration influencing neratinib response via PI3K activation illustrate potential mechanisms of treatment resistance that can be overcome through a combination therapy of neratinib and PI3Kα inhibitors.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Despite some existing insights into mutation-treatment interactions,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; comprehensive investigations into the broader landscape of genetic interactions and their implications for treatment outcomes remain crucial.&lt;/p&gt;&lt;p&gt;These challenges necessitate a comprehensive investigation of genetic interactions, especially co-occurrences, and their association with treatment outcomes in breast cancer. Accordingly, we developed a comprehensive network of genetic interactions specific to breast cancer, identifying 50 instances of co-occurrence and 30 instances of mutual exclusivity.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; This network not only reaffirms known associations, such as the co-occurring &lt;i&gt;TP53&lt;/i&gt; mutation and &lt;i&gt;MYC&lt;/i&gt; copy number amplification, as well as mutually exclusive mutations between &lt;i&gt;PIK3CA&lt;/i&gt; and &lt;i&gt;AKT1&lt;/i&gt;, but also unveils novel genetic interactions, such as the co-occurring &lt;i&gt;TP53&lt;/i&gt; mutation and &lt;i&gt;MYB&lt;/i&gt; copy number amplification, previou","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144687910","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":"Glutamate as a therapeutic strategy to promote liver regeneration","authors":"María del Mar Rigual,&nbsp;Nabil Djouder","doi":"10.1002/ctm2.70421","DOIUrl":"https://doi.org/10.1002/ctm2.70421","url":null,"abstract":"&lt;p&gt;Rigual MdM, Djouder N. Glutamate as a therapeutic strategy to promote liver regeneration. &lt;i&gt;Clin Transl Med&lt;/i&gt;. 2025;00:e70421. https://doi.org/10.1002/ctm2.70421&lt;/p&gt;&lt;p&gt;The intrinsic regenerative capacity of the liver is crucial for recovery following injury, surgical resection, or transplantation. However, in patients with chronic liver disease or extensive hepatectomy, this capacity is often compromised, limiting therapeutic outcomes. Recent findings uncover a novel, metabolically driven mechanism of liver regeneration centred on glutamate signalling. Following hepatic injury, downregulation of unconventional prefoldin RPB5 interactor 1 (URI1) in pericentral hepatocytes leads to reduced glutamine synthetase (GS) activity and elevated systemic glutamate levels. This circulating glutamate activates bone marrow-derived macrophages, which migrate to the liver, stabilise hypoxia-inducible factor 1-alpha (HIF1α), and secrete Wnt3, initiating YAP1-driven hepatocyte proliferation and effective tissue repair. Importantly, glutamate supplementation was shown to robustly promote liver regeneration and increase survival in preclinical models, including cirrhosis and 90% hepatectomy. These findings identify a clinically actionable metabolic-immune axis and suggest that oral physiological concentration of glutamate supplementation could serve as a safe, affordable adjunct therapy for patients undergoing liver resection, transplantation, or managing chronic liver failure. In addition, the potential development of URI1 inhibitors could offer an additional pharmacological approach to modulate this regenerative pathway. Together, this work represents a paradigm shift in regenerative hepatology, establishing glutamate as a key therapeutic driver of liver repair and opening the door to clinical trials aiming to validate its efficacy and safety in human patients.&lt;/p&gt;&lt;p&gt;The liver is a vital organ responsible for metabolic homeostasis and detoxification, rendering it particularly susceptible to injury from alcohol, drugs, environmental toxins, and dietary factors. Remarkably, despite continuous exposure to harmful agents, the liver possesses a unique and robust regenerative capacity. Hepatocytes, the principal functional cells of the liver and the cells that shoulder the regenerative process, are typically quiescent under normal conditions but can rapidly proliferate in response to tissue damage.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;This regenerative process is crucial for recovery from acute damage and for maintaining liver mass and function.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; However, after chronic or repeated injury, the liver regenerative capacity declines significantly, impairing the classic regenerative program and limiting the ability of hepatocytes to proliferate. This reduction in regenerative potential is a major clinical problem, especially for patients with chronic liver diseases or liver cancer requiring surgical resection, such as tumour removal or liver transp","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 7","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666152","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}