Journal of Experimental & Clinical Cancer Research最新文献

{"title":"PSMA-targeted theranostic nanoplatform achieves spatiotemporally precise therapy and triggers ferroptosis in prostate cancer treatment.","authors":"Linxue Zhang, Qi Sun, Dongxin Zheng, Xiang Huang, Zhong Yu, Zhongwen Lan, Wei Xiong, Ke Sun, Ruiji Liu","doi":"10.1186/s13046-025-03530-4","DOIUrl":"10.1186/s13046-025-03530-4","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"272"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202017","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":"Epigenetic regulation in gynecological cancers: a paradigm shift in immunotherapy strategies.","authors":"Chenyuan Zhao, Yang Liu, Zhuo Cui","doi":"10.1186/s13046-025-03509-1","DOIUrl":"10.1186/s13046-025-03509-1","url":null,"abstract":"<p><p>Recent advances in immunotherapy have transformed the therapeutic landscape of gynecological cancers; however, durable responses remain limited by tumor heterogeneity and immune evasion mechanisms. Emerging evidence highlights epigenetic modifications comprising of DNA methylation, histone modifications, and RNA methylation as pivotal regulators of the tumor immune microenvironment and immunotherapy efficacy. This review comprehensively explores how these epigenetic alterations modulate immune cell infiltration, antigen presentation, immune checkpoint expression, and tumor immunogenicity across cervical, ovarian, and endometrial cancers. We also delineate the impact of specific epigenetic enzymes, such as DNMTs, HDACs, BET and RNA methyltransferases, in shaping immune responses and discuss the therapeutic potential of targeting these regulators to sensitize tumors to immune checkpoint inhibitors, cancer vaccines, cytokine based treatments and adoptive T-cell therapies. Furthermore, we examine the integration of epigenetic agents such as DNMT and HDAC inhibitors with immunotherapies in preclinical and clinical settings, emphasizing their synergistic capacity to overcome immunoresistance. By illuminating the interplay between epigenetic regulation and immune dynamics, this review underscores a paradigm shift toward precision immunoepigenetic strategies, offering a promising framework for enhancing therapeutic outcomes in gynecological malignancies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"275"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202062","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":"DUSP8 as a regulator of glioblastoma stem-like cell contribution to tumor vascularization.","authors":"Giorgia Castellani, Mariachiara Buccarelli, Quintino Giorgio D'Alessandris, Gabriele De Luca, Ramona Ilari, Francesca Pedini, Maurizio Martini, Cristiana Mollinari, Claudio Tabolacci, Gabriele Ricciardi, Emanuela Germanà, Valentina Lulli, Alessandra Boe, Mauro Biffoni, Giovanna Marziali, Roberto Pallini, Lucia Ricci-Vitiani","doi":"10.1186/s13046-025-03515-3","DOIUrl":"10.1186/s13046-025-03515-3","url":null,"abstract":"<p><p>Glioblastomas (GBMs) are highly vascularized cancers. Transdifferentiation of GBM stem-like cells (GSCs) into GSC-derived endothelial cells (GdECs) contributes to GBM neovascularization. To dissect the molecular mechanisms and the signaling pathways underlying GSC contribution to tumor vascularization, we identified a three miRNA signature able to discriminate GSCs from GdECs by regulating different signaling pathways. DUSP8 resulted as the common target of the miRNA signature identified and is negatively regulated by miR-1825. DUSP8 is emerging as a critical negative regulator MAPKs pathway and is involved in cell oxidative stress response and apoptosis, as well as, in several diseases, including cancer. In GBM patients, DUSP8 and miR-1825 expression are inversely correlated and DUSP8 down-regulation is significantly associated with higher microvascular density and poor overall survival. Exploring the impact of DUSP8 in GSC transdifferentiation, we demonstrated that DUSP8 down-regulation interferes with MAPK pathway and affects soluble factor release. In vitro DUSP8 modulation experiments showed that DUSP8 enforced expression impairs GdEC ability to form tube-like structures. Gene expression variations induced by DUSP8 modulation affect transcripts associated with EMT pathway, confirming that DUSP8 shutdown and, therefore, the activation of MAPK pathway, is mandatory to GSC transdifferentiation. In vivo experiments demonstrated that both DUSP8 enforced expression and silencing dramatically affect gliomagenesis. Dissecting the molecular mechanisms underlying the contribution of GSCs to tumor angiogenesis might represent a chance to develop new and more efficient antiangiogenic therapeutic protocols for GBM treatment. Our findings provide a strong rationale to develop therapeutic strategies based on modulation of DUSP8 for GBM treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"269"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201992","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":"FSTL3 is a biomarker of poor prognosis and associated with immunotherapy resistance in ovarian cancer.","authors":"Maeva Chauvin, Estelle Tromelin, Julien Roche-Prellezo, Hyshem H Lancia, Marie-Charlotte Meinsohn, Caroline Coletti, Ngoc Minh Phuong Nguyen, Virginie Lafont, Henri-Alexandre Michaud, Ranjan Mishra, Nathalie Bonnefoy, Laurent Gros, David Pépin","doi":"10.1186/s13046-025-03425-4","DOIUrl":"10.1186/s13046-025-03425-4","url":null,"abstract":"<p><p>High-grade serous ovarian carcinoma (HGSOC) is associated with high mortality rates due to late-stage diagnosis and limited treatment options. We investigated the role of FSTL3 in ovarian cancer progression both as a prognostic biomarker and as a potential therapeutic target.We measured levels of follistatin (FST) and follistatin-like 3 (FSTL3) in 96 ovarian cancer patient ascites samples and found that FSTL3 overexpression was more predominant than FST and associated with poorer survival outcomes. Mice implanted with an HGSOC syngeneic cell line bearing common alterations in ovarian cancer (KRAS^{G12 V}, P53^R172H, CCNE1^oe, AKT2^oe) had increasing levels of FST and FSTL3 in serum during tumor growth. Further alteration of this model to generate a knockout of FST (KPCA.FSTKO) and an overexpression of human FSTL3 (KPCA.FSTKO_hFSTL3) revealed that FSTL3 expression was associated with a more fibrotic tumor microenvironment, correlating with an increased abundance of cancer-associated myofibroblasts (myCAFs), and cancer cells with a more mesenchymal phenotype. Tumors overexpressing FSTL3 also had significantly less immunocyte infiltration, reduced intratumoral T-cell abundance, and increased CD8+ T cell exhaustion. FSTL3 overexpression completely abrogated tumor response to PPC treatment (Prexasertib combined with PD-1 and CTLA-4 blockade) compared to controls, suggesting that FSTL3 may be involved in immunotherapy resistance. In conclusion, this study suggests a role for FSTL3 as a prognostic marker and as therapeutic target in HGSOC, where it may play a role in promoting a mesenchymal tumor phenotype, maintaining an immunosuppressive tumor microenvironment, and driving immunotherapy resistance.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"271"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202026","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":"Cancer-associated fibroblast promotes tamoxifen resistance in estrogen receptor positive breast cancer via exosomal LncRNA PRKCQ-AS1/miR-200a-3p/MKP1 axis-mediated apoptosis suppression.","authors":"Chenghui Wu, Xi Sun, Yujie Lu, Haoyu Wang, Zhengyuan Yu, Zheng Wang, Renhong Huang, Yihua Jin, Xing Chen, Haixia Xie, Yu Zong, Kunwei Shen, Min Jiang, Yujie Tang, Xiaosong Chen","doi":"10.1186/s13046-025-03529-x","DOIUrl":"10.1186/s13046-025-03529-x","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"274"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202034","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 cells promote immunosuppression in ovarian cancer via a positive feedback loop with MDSCs through the SAA1-IL-1β axis.","authors":"Haoran Hu, Meiqin Yang, Baoyou Huang, Jianyi Ding, Yashi Zhu, Xinxin Xu, Bo Yin, Huijuan Zhou, Tiefeng Huang, Mengjie Li, Yifan Kou, Zilale Rahim, Ang Li, Wei Wang, Lingfei Han","doi":"10.1186/s13046-025-03536-y","DOIUrl":"10.1186/s13046-025-03536-y","url":null,"abstract":"<p><strong>Background: </strong>Immune tolerance in epithelial ovarian cancer (EOC) enables cancer cells to evade immune surveillance. Myeloid-derived suppressor cells (MDSCs), as crucial immunosuppressive regulators, shape the tumor microenvironment and contribute to resistance against immunotherapy. However, the regulatory mechanisms of MDSCs in ovarian cancer remain poorly understood.</p><p><strong>Methods: </strong>We examined the presence and distribution of MDSCs in peripheral blood and tumor tissues from EOC patients. Transcriptomic analysis was performed on ovarian cancer cells co-cultured with MDSCs. The role of Serum Amyloid A1 (SAA1) was investigated through in vitro functional assays, co-culture experiments, and in vivo mouse models.</p><p><strong>Results: </strong>MDSCs were enriched in both peripheral blood and tumor tissues of EOC patients. SAA1 was significantly upregulated in ovarian cancer cells after interaction with MDSCs and confirmed in tumor samples and cell lines. Functionally, SAA1 promoted cancer cell proliferation, migration, and invasion. It also recruited MDSCs via TLR2/4, induced the differentiation of granulocyte-monocyte progenitors (GMPs), and stimulated IL-1β secretion, which in turn enhanced SAA1 expression, forming a positive feedback loop. In vivo, SAA1 promoted tumor progression and ascites formation. Clinically, high levels of SAA1, IL-1β, and CD33⁺ MDSCs correlated with poor survival.</p><p><strong>Conclusion: </strong>This study uncovers a novel SAA1-IL-1β feedback loop that promotes immunosuppression and progression in ovarian cancer. These findings provide insight into tumor-immune interactions and suggest a potential biomarker and therapeutic target for EOC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"277"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201976","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":"Mechanistic models position ceritinib as a nuclear integrity disrupting therapy in pediatric liver tumors.","authors":"Salih Demir, Thomas Kessler, Alina Hotes, Beate Häberle, Eiso Hiyama, Tomoro Hishiki, Emilie Indersie, Sophie Branchereau, Christian Vokuhl, Mathurin Dorel, Hans Lehrach, Bodo Lange, Stefano Cairo, Roland Kappler","doi":"10.1186/s13046-025-03535-z","DOIUrl":"10.1186/s13046-025-03535-z","url":null,"abstract":"<p><strong>Background: </strong>Pediatric liver tumors with high-risk features pose therapeutic challenges, necessitating the development of more targeted and effective treatment strategies. Computational modeling of virtual patients and in silico drug response simulations, based on properly trained mechanistic models, is a powerful strategy to predict new treatment options. We aimed to leverage patient-specific mechanistic cell models to identify therapeutic alternatives for pediatric patients with high-risk liver tumors.</p><p><strong>Methods: </strong>We generated digital twins of high-risk pediatric liver tumor patients by integrating clinical, genetic, and transcriptomic data and performed computational drug response simulations using mechanistic models. We validated the therapeutic potential of ceritinib in patient-derived xenograft models both in vitro and in vivo and used fluorescence microscopy-based imaging for functional analyses.</p><p><strong>Results: </strong>Mechanistic models trained with digital twins of high-risk pediatric liver tumor patients identified ceritinib as the most effective treatment option through iterated in silico drug response simulations. Validation on a comprehensive drug-testing platform demonstrated that ceritinib, unlike other ALK receptor tyrosine kinase inhibitors with lower prediction scores, inhibited tumor growth by targeting non-canonical kinases. Mechanistically, ceritinib suppressed expression of nucleoporins, essential components of the nuclear pore complex overexpressed in pediatric liver tumors, consequently leading to the disruption of nuclear membrane integrity, perinuclear accumulation of mitochondria, production of reactive oxygen species, and induction of apoptosis. In patient-derived xenograft mouse models, ceritinib reduced tumor burden and extended survival by promoting cell death.</p><p><strong>Conclusion: </strong>This study demonstrates the successful application of mechanistic models on virtual patients to position ceritinib as a promising therapeutic agent for high-risk pediatric liver tumors, highlighting its impact on key kinases implicated in tumor aggressiveness and its ability to compromise nuclear integrity.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"268"},"PeriodicalIF":12.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088070","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: HMGA1-TRIP13 axis promotes stemness and epithelial mesenchymal transition of perihilar cholangiocarcinoma in a positive feedback loop dependent on c-Myc.","authors":"Zhipeng Li, Jialiang Liu, Tianli Chen, Rongqi Sun, Zengli Liu, Bo Qiu, Yunfei Xu, Zongli Zhang","doi":"10.1186/s13046-025-03526-0","DOIUrl":"10.1186/s13046-025-03526-0","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"267"},"PeriodicalIF":12.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071117","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: Elucidating the role of N‑myristoylation in the excessive membrane localization of PD‑L1 in hypoxic cancers and developing a novel NMT1 inhibitor for combination with immune checkpoint blockade therapy.","authors":"Haoming Zhao, Zhen Zhang, Chaojun Zhang, Hexin Ma, Qingqing Wan, Xinran Zhao, Xu Wang, Ming Yan, Haiyan Guo, Jianjun Zhang, Wantao Chen","doi":"10.1186/s13046-025-03533-1","DOIUrl":"10.1186/s13046-025-03533-1","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"266"},"PeriodicalIF":12.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994216","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":"Cancer-associated fibroblast derived CXCL14 drives cisplatin chemoresistance by enhancing nucleotide excision repair in bladder cancer.","authors":"Tinghao Li, Kunyao Zhu, Hang Tong, Yan Sun, Junlong Zhu, Zijia Qin, Junrui Chen, Linfeng Wu, Xiaoyu Zhang, Aimin Wang, Xin Gou, Hubin Yin, Weiyang He","doi":"10.1186/s13046-025-03487-4","DOIUrl":"10.1186/s13046-025-03487-4","url":null,"abstract":"<p><strong>Background: </strong>A significant challenge in bladder cancer treatment is primary chemoresistance, in which cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a pivotal role. While the contributions of CAFs to tumor progression and drug resistance are well established, the precise molecular mechanisms by which they induce chemoresistance remain unclear. A comprehensive understanding of the effect of TME modulation-particularly through CAFs-on the chemotherapeutic response is crucial for developing effective strategies to overcome chemoresistance and improve patient survival.</p><p><strong>Methods: </strong>Primary fibroblasts were isolated from paired clinical samples of bladder cancer tissues and adjacent normal tissues to identify key CAF-derived secretory factors. Bioinformatics analysis, semiquantitative RT‒qPCR, and dual-luciferase reporter assays were subsequently used to investigate the functional role and mechanistic basis of CXCL14 in chemoresistance. The therapeutic relevance of these findings was further evaluated through in vitro and in vivo models, including ex vivo patient-derived organoid (PDO) models, by assessing cisplatin sensitivity and validating therapeutic targeting of the CXCL14-CCR7-STAT3 axis with small molecule inhibitors.</p><p><strong>Results: </strong>Compared to normal fibroblasts and CAFs from nonchemoresistance groups, CAFs derived from cisplatin-resistant patients demonstrated significantly greater paracrine-mediated induction of chemoresistance. Mechanistically, CAF-secreted CXCL14 engaged CCR7 on bladder cancer cells, triggering STAT3 phosphorylation and consequently upregulating the DNA repair gene ERCC4 to promote cisplatin resistance. In vivo validation confirmed that pharmacological CCR7 or STAT3 inhibition markedly reversed chemoresistance and potentiated cisplatin-induced tumor cell death. Notably, STAT3 activation mediated the overexpression of the glycolytic enzymes HK2 and LDHA, resulting in greater glycolytic flux in resistant cells. This metabolic reprogramming further facilitated the transdifferentiation of normal fibroblasts into CXCL14-secreting CAFs, establishing a self-reinforcing feedback loop that sustains chemoresistance.</p><p><strong>Conclusion: </strong>The CXCL14/CCR7/STAT3 axis critically mediates cisplatin resistance in bladder cancer through dual modulation of DNA repair and glycolytic metabolism. Therapeutic cotargeting of this pathway with CCR7 or STAT3 inhibitors combined with cisplatin represents a promising strategy to overcome chemoresistance and improve clinical outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"265"},"PeriodicalIF":12.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12406535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977164","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}