Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Genome-Wide Methylation Sequencing to Identify DNA Methylation Markers for Early-stage Hepatocellular Carcinoma in Liver and Blood.","authors":"Siyu Fu, Ruben G Boers, Joachim B Boers, Pam E van der Meeren, Jean Helmijr, Vanja de Weerd, Michail Doukas, Maurice Jansen, Bettina E Hansen, Roeland F de Wilde, Dave Sprengers, Joost Gribnau, Saskia M Wilting, José D Debes, Andre Boonstra","doi":"10.1186/s13046-025-03412-9","DOIUrl":"10.1186/s13046-025-03412-9","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is associated with a poor 5-year survival mainly due to detection at late stages. Better non-invasive surveillance methods are needed to improve early detection and maximize survival. We performed a strict assessment of DNA methylation markers (DMMs) for HCC detection.</p><p><strong>Methods: </strong>A total of 385 samples from liver tissues and blood were analyzed. Genome-wide Methylated DNA sequencing (MeD-seq) was initially performed on 46 liver tissues, followed by the validation using quantitative methylation-specific PCR (qMSP) on 175 liver tissues. The selected DMMs with and without ASAP/GAAD score were further evaluated in 180 blood samples. Additionally, MeD-seq was performed to validate the results on blood.</p><p><strong>Results: </strong>MeD-seq revealed a substantial number of differentially methylated regions (DMRs) in HCC tissues compared to non-HCC controls. By qMSP, the top 5 DMMs demonstrated strong performance in distinguishing cirrhotic HCC from cirrhosis controls in tissue (AUC 0.842 to 0.957). However, evaluation of these DMMs in blood showed lower performance in early HCC detection compared to cirrhosis in both the training (sensitivity 26.7-43.3%, 81.3% specificity) and validation cohorts (sensitivity 16.2-43.2%, 85.7% specificity). The addition of DMMs to the ASAP/GAAD score only provided an additional 5.4% sensitivity in the validation cohort compared to the ASAP/GAAD score alone. These findings were confirmed using MeD-seq analysis in blood samples, which revealed no detectable DMRs between cirrhotic HCC and cirrhosis controls. Interestingly, DNA methylation patterns in blood of healthy individuals differed strongly from both groups (cirrhosis and cirrhotic HCC).</p><p><strong>Conclusion: </strong>DNA methylation patterns in liver tissue were distinctly different between HCC and controls. In blood, DMMs contributed minimally to early-stage HCC detection compared to cirrhosis, whether used alone or in combination with the ASAP/GAAD score. It is likely that high baseline DNA methylation related to cirrhosis and possibly the low input of tumor-related DNA impacts the use of DMMs in early HCC detection in blood.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"144"},"PeriodicalIF":11.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081538","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":"Comparative analysis of circulating tumor cells in prostatic plexus and peripheral blood of patients undergoing prostatectomy.","authors":"Gresa Emurlai, Randi M Pose, Nikhil Kalra, Cornelia Coith, Sandra Lenz, Pierre Tennstedt, Markus Graefen, Stefan Werner, Sabine Riethdorf, Derya Tilki, Simon A Joosse, Klaus Pantel","doi":"10.1186/s13046-025-03397-5","DOIUrl":"10.1186/s13046-025-03397-5","url":null,"abstract":"<p><strong>Background: </strong>The potential influence of radical prostatectomy on tumor cell release into the blood circulation is an under-investigated area.</p><p><strong>Methods: </strong>One hundred three treatment-naïve patients with early-stage prostate cancer were recruited. Blood from the prostatic venous plexus was analyzed for the local release of tumor cells during radical prostatectomy. Simultaneously, systemic spread was assessed by the presence of circulating tumor cells (CTCs) in peripheral venous blood using both the EpCAM-dependent CellSearch and the size-dependent Parsortix systems in parallel. Tumor cells in the plexus blood and CTCs were detected by epithelial keratin expression and lack of CD45 leukocyte antigen.</p><p><strong>Results: </strong>Median counts of Keratin + /CD45- cells detected in peripheral blood with the CellSearch and Parsortix systems differed significantly (p = 0.0067) with higher sensitivity of the Parsortix System (16 vs 32% positive findings). Even if the results of both assays were combined, the median number of Keratin + /CD45- cells in the prostatic plexus blood was significantly higher than in the peripheral blood (97 vs. 2 per 7.5 ml, respectively, p < 0.0001). Keratin + /CD45- cells could be identified in 85% of prostate cancer patients in the prostatic plexus blood and in 42% of patients in peripheral blood during surgery without any significant correlation. Keratin + /CD45- cell clusters were identified in the prostatic plexus in 51.2% of patients but neither these clusters nor single Keratin + /CD45- cells were associated with biochemical relapse during follow-up. The presence (p = 0.0094) and number (p = 0.0153) of CTCs in the peripheral blood was significantly associated with PSA levels at initial diagnosis. Single-cell genome-wide sequencing by NGS showed copy number alterations (CNAs) in 15 out of 26 index CTCs originating from both the prostatic plexus and peripheral blood compartments.</p><p><strong>Conclusion: </strong>Combining different CTC enrichment principles increases the CTC detection rate in the peripheral blood of early-stage prostate cancer patients. Our study provides first evidence for a considerable local release of normal and malignant epithelial cells during prostatectomy, which, however, was neither associated with increased CTC detection in the peripheral blood nor with early biochemical recurrence. Longer follow up studies are required to assess whether local tumor cell spread might contribute to clinical outcome in prostate cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"143"},"PeriodicalIF":11.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056135","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":"Tie2 activity in cancer associated myofibroblasts serves as novel target against reprogramming of cancer cells to embryonic-like cell state and associated poor prognosis in oral carcinoma patients.","authors":"Paromita Mitra, Uday Saha, Kingsly Joshua Stephen, Priyanka Prasad, Subhashree Jena, Ankit Kumar Patel, Harshavardhan Bv, Santosh Kumar Mondal, Sillarine Kurkalang, Sumitava Roy, Arnab Ghosh, Shantanu Saha Roy, Jayasri Das Sarma, Nidhan Kumar Biswas, Moulinath Acharya, Rajeev Sharan, Pattatheyil Arun, Mohit Kumar Jolly, Arindam Maitra, Sandeep Singh","doi":"10.1186/s13046-025-03405-8","DOIUrl":"https://doi.org/10.1186/s13046-025-03405-8","url":null,"abstract":"<p><strong>Background: </strong>Myofibroblastic cancer-associated fibroblasts (CAF) in tumor stroma serves as an independent poor prognostic indicator, supporting higher stemness in oral cancer; however, the underlying biology is not fully comprehended. Here, we have explored the crucial role of Tunica Interna Endothelial Cell Kinase (Tie2/TEK) signaling in transition and maintenance of myofibroblastic phenotype of CAFs, and as possible link with the poor prognosis of head and neck squamous cell carcinoma (HNSCC) patients.</p><p><strong>Methods: </strong>Bulk and single cell RNA-sequencing (scRNAseq) methods and in-depth bioinformatic analysis were applied for CAF and cancer cells co-culture for studying molecular relationships. In vitro 3D-spheroid-forming ability, expression of stemness markers, in vivo tumor formation ability in zebrafish embryo and syngeneic mouse allografts formation was conducted to test stemness, upon targeting CAF-specific Tie2 activity by gene silencing or with small molecule inhibitor. Immunohistochemistry analysis was performed to locate the distribution of Tie2 and αSMA in primary tumors of oral carcinoma. Prognosis in HNSCC patient cohort from The Cancer Genome Atlas (TCGA) study was analysed based on single sample gene set enrichment score (ssGSEA) and Kaplan-Meier analysis.</p><p><strong>Results: </strong>Autocrine or exogenous TGFβ-induction in CAF led to the recruitment of histone deacetylase 2 (HDAC2) on the promoter of Tie2-antagonist, Angiopoietin-2 (ANGPT2), resulting in its downregulation, leading to phosphorylation of Tie2 (Y992) and subsequent activation of SRC (Y418). This led to SRC/ROCK mediated αSMA-positive stress-fiber formation with gain of myofibroblast phenotype. The CAF-specific Tie2-signaling was responsible for producing embryonic-like cell state in co-cultured cancer cells; with enhanced tumor initiating ability. Tie2 activity in CAF exerted the dynamic gene expression reprogramming, with the upregulation of 'cell migration' and downregulation of 'protein biosynthesis' related gene-regulatory-network modules in malignant cells. The AUCell scores calculated for gene signatures derived from these modules showed significant concordance in independently reported scRNAseq studies of HNSCC tumors and significant association with poor prognosis in HNSCC patient cohort.</p><p><strong>Conclusions: </strong>CAF-specific Tie2 activity may serve as direct stromal-target against cancer cell plasticity leading to poor prognosis of oral cancer patients. Overall, our work has provided wider applicability of Tie2-specific functions in tumor biology, along with its known role in endothelial cell-specific function.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"142"},"PeriodicalIF":11.4,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990570","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":"Tumor cell-intrinsic BIN1 deficiency promotes the immunosuppression and impedes ferroptosis of non-small cell lung cancer via G3BP1-mediated degradation of STAT1.","authors":"Jiali Wang, Yunlong Jia, Tianxu Liu, Xinyan Liu, Shuxian Yin, Jiaqi Chen, Xiaoqing Xu, Yi Zhang, Lihua Liu","doi":"10.1186/s13046-025-03404-9","DOIUrl":"https://doi.org/10.1186/s13046-025-03404-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Tumors often evade immune surveillance by limiting T cell infiltration. In non-small cell lung cancer (NSCLC), increased infiltration of CD8&lt;sup&gt;+&lt;/sup&gt; T cells is associated with a favorable response to immunotherapy. While BIN1 is recognized as a tumor suppressor gene, its role in shaping the tumor microenvironment in NSCLC has yet to be fully clarified.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;To investigate the relationship between BIN1 expression and CD8&lt;sup&gt;+&lt;/sup&gt;T cell infiltration in NSCLC, we performed a comprehensive data analysis utilizing clinical information from NSCLC patients. BIN1 expression levels in NSCLC tissues were evaluated, and their correlation with CD8&lt;sup&gt;+&lt;/sup&gt;T cells infiltration and patient survival outcomes was examined. Loss-of-function strategies targeting BIN1 were applied in syngeneic NSCLC mouse models to assess its functional significance. Tumor growth was monitored, and immune cell populations were analyzed in terms of frequency and functionality through mass cytometry and flow cytometry techniques. Cytokine secretion was profiled using multiplex assays. Additionally, RNA sequencing, immunoprecipitation-mass spectrometry, and molecular docking were employed to confirm direct interactions between BIN1 and cytokine-encoding genes. Finally, the regulatory role of BIN1 in ferroptosis in NSCLC cells were explored using metabolomics analysis, ROS measurement, and MDA detection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We observed that BIN1 expression is downregulated in NSCLC tumor tissues, with its reduced expression strongly associated with advanced disease progression and poor prognosis. Bioinformatics analysis of immune infiltration in human NSCLC samples revealed a positive correlation between BIN1 expression in NSCLC tissues and CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration. Furthermore, the prognostic impact of BIN1 on NSCLC patients is strongly linked to the level of CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration. In syngeneic mouse models, the knockout of BIN1 in NSCLC cells significantly inhibited CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration and impaired their cytotoxic function, facilitating tumor immune evasion. Mechanistically, we demonstrated that BIN1 directly interacts with G3BP1, and its knockout stabilizes G3BP1. This, in turn, promotes STAT1 degradation and reduces the secretion of T cell-recruiting chemokines such as CXCL10 and CCL5. Finally, our findings reveal that BIN1 influences ferroptosis in NSCLC cells through the G3BP1/STAT1/GSH pathway, thereby regulating NSCLC cell proliferation, migration, and invasion.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study highlights the crucial role of the BIN1/G3BP1/STAT1/CD8&lt;sup&gt;+&lt;/sup&gt; tumor-infiltrating lymphocyte signaling pathway in the progression of NSCLC and its mechanisms of immune evasion. This fundings lay a foundation for the development of BIN1-targeted therapies aimed at improving tumor immunogenicity and transforming immunologically \"cold\" NSCLC into a more","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"141"},"PeriodicalIF":11.4,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047927","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":"Liquid biopsy in gynecological cancers: a translational framework from molecular insights to precision oncology and clinical practice.","authors":"Canio Martinelli, Alfredo Ercoli, Giuseppe Vizzielli, Sharon Raffaella Burk, Maria Cuomo, Vrunda Satasiya, Housem Kacem, Simone Braccia, Giulio Mazzarotti, Irene Miriello, Manuela Nana Tchamou, Stefano Restaino, Martina Arcieri, Alice Poli, Veronica Tius, Silvana Parisi, Stefano Pergolizzi, Giuseppe Iatì, Chiara Conti Nibali, Cristina Pizzimenti, Ludovica Pepe, Antonio Ieni, Salvatore Cortellino, Antonio Giordano","doi":"10.1186/s13046-025-03371-1","DOIUrl":"https://doi.org/10.1186/s13046-025-03371-1","url":null,"abstract":"<p><p>Liquid biopsy offers a noninvasive method to identify and monitor tumor-derived biomarkers, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, microRNAs, and tumor-educated platelets, that provide real-time insights into the biological behavior of gynecological cancers. The detection of these markers has the potential to revolutionize cancer management by enabling earlier detection, providing novel data to personalize treatments, and predicting disease recurrence before clinical imaging and predicting disease recurrence before clinical imaging can confirm progression, thereby also guiding complex clinical decision-making. However, because this new \"omics\" layer introduces additional complexity, it must be fully understood, from its biological rationale to technical development and clinical integration, to prevent confusion or misapplication. That is why, focusing on 14 critical fields of inquiry, our goal is to map the current state of liquid biopsy from bench to bedside while highlighting practical considerations for clinical integration. Each topic integrates recent advances in assay sensitivity, biomarker variability, and data interpretation, underscoring how standardized protocols and robust analytical methods are pivotal for reliable results. We then translate these findings into disease-specific insights, examining how liquid biopsy could refine early detection, minimal residual disease assessment, and therapy guidance in endometrial, cervical, and ovarian cancers. Although several FDA-approved assays and promising commercial tests illustrate the field's rapid evolution, many translational hurdles remain, including the need for harmonized protocols, larger prospective clinical trials, and cost-effectiveness analyses. Crucially, our synthesis clarifies the pivotal role of interdisciplinary collaboration. Oncologists, laboratory scientists, and industry partners must align on standardized procedures and clinically relevant endpoints. Without such coordination, promising biomarkers may remain confined to research settings, limiting their practical benefit. Taken together, our review offers a translational view designed to contextualize liquid biopsy in gynecological oncology.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"140"},"PeriodicalIF":11.4,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024107","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":"Targeted inhibition of PDGFRA with avapritinib, markedly enhances lenvatinib efficacy in hepatocellular carcinoma in vitro and in vivo: clinical implications.","authors":"Bixing Zhao, Yang Zhou, Niangmei Cheng, Xiaoyuan Zheng, Geng Chen, Xin Qi, Xiangzhi Zhang, Fei Wang, Qiuyu Zhuang, Yehuda G Assaraf, Xiaolong Liu, Yingchao Wang, Yongyi Zeng","doi":"10.1186/s13046-025-03386-8","DOIUrl":"10.1186/s13046-025-03386-8","url":null,"abstract":"<p><strong>Background: </strong>Lenvatinib, a tyrosine kinase receptor inhibitor, has emerged as a frontline therapeutic strategy for the management of advanced hepatocellular carcinoma (HCC). However, the modest response rate observed with lenvatinib and the rapid emergence of chemoresistance highlight the urgent need to elucidate the underlying molecular mechanisms. Herein we aimed at identifying the molecular mechanisms underlying lenvatinib resistance in HCC and investigated the efficacy of targeted combination therapies to surmount this chemoresistance.</p><p><strong>Methods: </strong>We utilized CRISPR/Cas9 gene knockout screening combined with transcriptome sequencing of lenvatinib-resistant HCC cell lines to identify resistance-associated genes. PDGFRA overexpression was validated in human lenvatinib-resistant HCC cells. We further corroborated the in vitro and in vivo role of PDGFRA in lenvatinib resistance using a PDGFRA inhibitor, avapritinib, employing a mouse orthotopic HCC model, patient-derived organoids (PDO), and patient-derived xenografts (PDX). The association between PDGFRA expression and patient prognosis was also assessed. Mechanistic studies were conducted to elucidate the signaling pathways contributing to lenvatinib resistance mediated by PDGFRA.</p><p><strong>Results: </strong>PDGFRA overexpression was identified as a key determinant of lenvatinib-resistance in HCC cells. Consistently, ectopic PGDGFRA overexpression conferred lenvatinib resistance upon HCC cells. Treatment with the PDGFRA inhibitor avapritinib sensitized HCC cells to lenvatinib in mouse orthotopic HCC, PDO, and PDX models. Increased PDGFRA expression was correlated with poor prognosis in HCC patients. Mechanistic studies revealed that lenvatinib treatment or PDGFRA overexpression promoted HCC resistance through the PTEN/AKT/GSK-3β/β-catenin signaling pathway.</p><p><strong>Conclusions: </strong>Our findings demonstrate that PDGFRA overexpression mediates lenvatinib resistance in HCC and that targeting PDGFRA with avapritinib, surmounts this resistance. Furthermore, the PTEN/AKT/GSK-3β/β-catenin pathway was implicated in lenvatinib resistance, providing a potential therapeutic strategy for HCC patients displaying lenvatinib resistance. Further clinical studies are warranted to validate these findings and to explore the clinical application of PDGFRA-targeted therapies in HCC treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"139"},"PeriodicalIF":11.4,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062979","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":"Decitabine co-operates with the IL-33/ST2 axis modifying the tumor microenvironment and improving the response to PD-1 blockade in melanoma.","authors":"Francesco Noto, Jacopo Mancini, Adriana Rosa Gambardella, Christina Curcio, Adele De Ninno, Sara Andreone, Carla Buccione, Maria Teresa D'Urso, Daniele Macchia, Anna Maria Pacca, Massimo Spada, Luca Businaro, Claudia Afferni, Fabrizio Mattei, Giovanna Schiavoni","doi":"10.1186/s13046-025-03381-z","DOIUrl":"https://doi.org/10.1186/s13046-025-03381-z","url":null,"abstract":"<p><strong>Background: </strong>IL-33 is an epithelial-derived alarmin with various roles in cancer. In melanoma, endogenous and exogenous IL-33 exert anti-tumor effects through the stimulation of several immune effector cells. In this study, we explored the combination of IL- 33 with Decitabine (DAC), a DNA methylation inhibitor that promotes immune recognition by re-activating silenced genes, for melanoma treatment.</p><p><strong>Methods: </strong>Multicellular spheroids, organ-on-chip technology and in vivo models were used to test the anti-tumor effects of IL-33 combined with DAC against mouse and human melanoma. Mice deficient for the IL-33 receptor ST2 (ST2^-/- mice) were employed to address the role of endogenous IL-33 signaling in DAC therapeutic response and tumor-immune crosstalk.</p><p><strong>Results: </strong>In multicellular spheroids of mouse and human melanoma cells, DAC alone inhibited tumor cell aggregation, suggesting its direct effect on tumor cells. In vivo, DAC combined with IL-33 reduced tumor growth and prolonged the survival of mice transplanted with melanoma cells, outperforming single treatments. Moreover, the combined DAC/IL-33 treatment was the most efficient in promoting immune recruitment (i.e., T cells and eosinophils) at the tumor site and induced the up-regulation of PD-1 resulting in better therapeutic response to PD-1 blockade in vivo. In a microfluidic-based competitive migration assay, DAC/IL- 33 treatment generated the strongest chemotactic response, attracting spleen cells from naïve wild-type, but not ST2^-/- mice, indicating that IL-33 signaling was crucial for immune cell recruitment. Accordingly, DAC failed to induce tumor immune infiltration and was ineffective in reducing tumor growth in ST2^-/- mice. In vivo, DAC increased the expression of ST2 and IL-33 at the tumor site, suggesting it may enhance endogenous IL-33 production. Methylation studies indicated that DAC increased the expression of IL-33 in mouse and human melanoma cells through demethylation of a transcription factor binding site located inside the IL33 gene.</p><p><strong>Conclusions: </strong>Our findings indicate that DAC effectively co-operates with IL-33/ST2 axis against melanoma through immune cell recruitment and epigenetic regulation of gene expression, thus remodeling the tumor immune microenvironment to overcome resistance to PD- 1 inhibition.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"137"},"PeriodicalIF":11.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057347","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":"Harnessing engineered extracellular vesicles for enhanced therapeutic efficacy: advancements in cancer immunotherapy.","authors":"Zheng Gong, Cheng Cheng, Chaonan Sun, Xiaoli Cheng","doi":"10.1186/s13046-025-03403-w","DOIUrl":"https://doi.org/10.1186/s13046-025-03403-w","url":null,"abstract":"<p><p>Extracellular vesicles (EVs), particularly engineered variants, have emerged as promising tools in cancer immunotherapy due to their inherent ability to modulate immune responses and deliver therapeutic agents with high specificity and minimal toxicity. These nanometer-sized vesicles, which include exosomes (Exos) and other subtypes, naturally participate in intercellular communication and are capable of carrying a diverse range of bioactive molecules, including proteins, lipids, RNAs, and metabolites. Recent advancements in the biogenesis of engineered EVs, such as strategies to modify their surface characteristics and cargo, have significantly expanded their potential as effective vehicles for targeted cancer therapies. Tailoring the contents of EVs, such as incorporating immunomodulatory molecules or gene-editing tools (GETs), has shown promising outcomes in enhancing anti-tumor immunity and overcoming the immunosuppressive tumor microenvironment (TME). Moreover, optimizing delivery mechanisms, through both passive and active targeting strategies, is crucial for improving the clinical efficacy of EV-based therapies. This review provides an overview of recent developments in the engineering of EVs for cancer immunotherapy, focusing on their biogenesis, methods of content customization, and innovations in cargo delivery. Additionally, the review addresses the challenges associated with the clinical translation of EV-based therapies, such as issues related to scalability, safety, and targeted delivery. By offering insights into the current state of the field and identifying key areas for future research, this review aims to advance the application of engineered EVs in cancer treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"138"},"PeriodicalIF":11.4,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048849","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":"Extracellular vesicle digital scoring assay for assessment of treatment responses in hepatocellular carcinoma patients.","authors":"Chen Zhao, Yi-Te Lee, Andrew Melehy, Minhyung Kim, Jacqueline Ziqian Yang, Ceng Zhang, Jina Kim, Ryan Y Zhang, Junseok Lee, Hyoyong Kim, Yong Ju, Yuan-Jen Tsai, Xianghong Jasmine Zhou, Steven-Huy B Han, Saeed Sadeghi, Richard S Finn, Sammy Saab, David S Lu, Jason Chiang, Jae-Ho Park, Todd V Brennan, Steven A Wisel, Manaf Alsudaney, Alexander Kuo, Walid S Ayoub, Hyunseok Kim, Hirsh D Trivedi, Yun Wang, Aarshi Vipani, Irene K Kim, Tsuyoshi Todo, Justin A Steggerda, Georgios Voidonikolas, Kambiz Kosari, Nicholas N Nissen, Rola Saouaf, Amit G Singal, Myung Shin Sim, David A Elashoff, Sungyong You, Vatche G Agopian, Ju Dong Yang, Hsian-Rong Tseng, Yazhen Zhu","doi":"10.1186/s13046-025-03379-7","DOIUrl":"https://doi.org/10.1186/s13046-025-03379-7","url":null,"abstract":"<p><strong>Background: </strong>There are no validated biomarkers for assessing hepatocellular carcinoma (HCC) treatment response (TR). Extracellular vesicles (EVs) are promising circulating biomarkers that may detect minimal residual disease in patients with treated HCC.</p><p><strong>Methods: </strong>We developed the HCC EV TR Score using HCC EV Digital Scoring Assay involving click chemistry-mediated enrichment of HCC EVs, followed by absolute quantification of HCC EV-specific genes by RT-digital PCR. Six HCC EV-specific genes were selected and validated through i) a comprehensive data analysis pipeline with an unprecedentedly large collection of liver transcriptome datasets (n = 9,160), ii) RNAscope validation on HCC tissues (n = 6), and iii) a pilot study on early- or intermediate-stage HCC and liver cirrhosis patients (n = 70). The performance of HCC EV TR Score was assessed in a phase-2 retrospective case-control study (n = 100).</p><p><strong>Results: </strong>HCC EV TR Scores, calculated from pre- and post-treatment plasma samples in the phase-2 case-control study, accurately differentiated post-treatment viable from nonviable HCC in the training (area under the ROC curve [AUROC] of 0.90, n = 49) and validation set (AUROC of 0.88, n = 51). At an optimal cutoff of 0.76 identified in the training set, HCC EV TR Score had high accuracy in detecting viable tumors (sensitivity: 76.5%, specificity: 88.2%) and found residual disease not initially observed on MRI in six patients with a median lead time of 63 days.</p><p><strong>Conclusions: </strong>This EV-based digital scoring approach shows great promise to augment cross-sectional imaging for the assessment of HCC treatment response.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"136"},"PeriodicalIF":11.4,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12044846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056659","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":"Epithelial-to-mesenchymal transition drives cancer genomic instability.","authors":"Julienne L Carstens, Sara Lovisa","doi":"10.1186/s13046-025-03402-x","DOIUrl":"https://doi.org/10.1186/s13046-025-03402-x","url":null,"abstract":"<p><p>Epithelial-to-Mesenchymal Transition (EMT) is a form of embryonic cell plasticity reactivated in adult cells during injury and cancer. A recent study by Perelli et al. demonstrates that EMT confers an evolutionary advantage to tumors by inducing chromosomal instability, structural genomic rearrangements and chromothripsis, thus favoring the emergence of high-fitness malignant clones.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"135"},"PeriodicalIF":11.4,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022677","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}