Journal of Experimental & Clinical Cancer Research最新文献

{"title":"High-throughput drug screening in advanced pre-clinical 3D melanoma models identifies potential first-line therapies for NRAS-mutated melanoma.","authors":"Cristian Angeli, Demetra Philippidou, Eliane Klein, Christiane Margue, Sagarika Ghosh, Maria Lorena Cordero Maldonado, Natascia Tiso, Giovanni Risato, Fizza Irfan, Bruno Santos, Meritxell Cutrona, Joanna Patrycja Wroblewska, Stephanie Kreis","doi":"10.1186/s13046-025-03539-9","DOIUrl":"https://doi.org/10.1186/s13046-025-03539-9","url":null,"abstract":"<p><strong>Background: </strong>Despite significant advances in targeted (BRAFi + MEKi) and immune (anti-PD1/PD-L1, anti-CTLA4, and anti-LAG3) therapies, treatment options for NRAS^mut melanoma remain limited. Currently, NRAS^mut patients rely on immune checkpoint inhibitors, classical chemotherapy, and off-label MEK inhibitors, with over 50% experiencing rapid disease progression. One of the key challenges in developing effective targeted therapies is the lack of preclinical models that accurately recapitulate the tumor microenvironment (TME) and the intrinsic resistance of melanoma cells bearing NRAS mutations.</p><p><strong>Methods: </strong>To address this, we performed high-throughput screening (HTS) of over 1,300 compounds in 3D NRAS^mut melanoma spheroids. A multi-step analysis was performed to identify hits, which were further tested by performing drug-response curve (DRC) analysis. Most promising compounds were further validated using mono- and co-culture 3D in vitro models that mimic three main metastatic sites in melanoma, such as skin/dermal, lung, and liver, utilizing spheroid and hydrogel systems. Ultimately, validation was conducted using zebrafish xenograft models to enable a more refined and accurate assessment of drug response.</p><p><strong>Results: </strong>High-throughput drug screening of NRAS^mut melanoma spheroids identified 17 candidate compounds, which were subsequently validated through DRC analyses. Among the most promising drugs, Daunorubicin HCl (DH) and Pyrvinium Pamoate (PP) were selected for further investigation, demonstrating potent anti-melanoma activity in advanced 3D co-culture systems and zebrafish xenograft models. Notably, PP demonstrated higher cytotoxicity compared to Trametinib, the off-label MEK inhibitor, with an inhibitory effect on AKT and invasive behavior in the patient-derived metastatic melanoma cell lines. Additionally, combinatorial treatment with Trametinib resulted in additive effects on cell proliferation and viability. Importantly, both compounds showed similar efficacy in NRAS^mut and BRAF^wt/NRAS^wt melanoma cell lines that were resistant to Trametinib (MEK inhibitor).</p><p><strong>Conclusions: </strong>Using advanced 3D melanoma models that incorporate key TME elements and zebrafish xenograft models, this study highlights the potential of Daunorubicin HCl and Pyrvinium Pamoate as novel first-line therapies for NRAS^mut melanoma, with a noteworthy effect also on MEKi-resistant cells. These findings support drug repurposing strategies and underscore the importance of physiologically relevant preclinical models in identifying effective therapies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"278"},"PeriodicalIF":12.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TEAD3 + high-risk melanoma cells crosstalk with GAS6 + macrophages via the GAS6-TYRO3 ligand-receptor axis to modulate propionate metabolism and drive melanoma progression.","authors":"Yongjin Fang, Xiaofan Xu, Rihui Lu, Ye Huang, Xinshen Dai, Pucheng Huang, Xuefeng Fu, Pan Zhuge","doi":"10.1186/s13046-025-03542-0","DOIUrl":"https://doi.org/10.1186/s13046-025-03542-0","url":null,"abstract":"<p><strong>Background: </strong>Melanoma, a highly heterogeneous malignancy, remains refractory to conventional therapies due to poorly defined molecular and metabolic drivers. Short-chain fatty acid (SCFA) metabolism influences tumor progression, yet its role in melanoma subtypes and clinical outcomes is unclear. This study aims to delineate melanoma subgroups driven by SCFA metabolic dysregulation and identify mechanisms underlying their aggressiveness.</p><p><strong>Methods: </strong>Using non-negative matrix factorization (NMF), we clustered 468 TCGA melanoma samples into six subgroups based on SCFA-related gene sets (GO:0019745, GO:0019746, GO:0006085). Survival, differential expression, and pathway analyses were performed to characterize high-risk subgroups. Key drivers were validated via CRISPR/Cas9, siRNA knockdown, and immunohistochemistry. Single-cell RNA-seq (GSE215120) and spatial transcriptomics elucidated tumor-microenvironment crosstalk. Metabolic profiling, Seahorse assays, and myeloid-specific GAS6 knockout models were employed to dissect mechanisms.</p><p><strong>Results: </strong>NMF clustering revealing a high-risk subtype (Group 6) with dysregulated short-chain fatty acid (SCFA) metabolism and poor survival. Group 6 exhibited upregulation of GLTP and RAPGEFL1, enrichment in melanogenesis, Hippo signaling, and skin/lipid metabolism pathways. Through integrative analysis, TEAD3 emerged as a key risk driver, with high expression correlating with poor prognosis. Functional validation demonstrated that TEAD3 knockout suppressed melanoma proliferation, migration, and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Single-cell RNA sequencing of acral melanoma revealed TEAD3-enriched tumor cells interacting with M2 macrophages via the GAS6-TYRO3 axis. Mechanistically, GAS6 + macrophages exhibited hypermetabolic phenotypes (elevated glycolysis/OXPHOS) that fueled GAS6 secretion. GAS6-TYRO3 signaling in TEAD3 + cells drove tumor aggressiveness by rewiring propionate metabolism, inducing methylmalonic acid accumulation via Mmut upregulation. Targeting this axis in myeloid-specific GAS6 knockout mice enhanced anti-PD-1 efficacy, boosting CD8 + T cell infiltration and survival.</p><p><strong>Conclusion: </strong>We define a TEAD3-driven melanoma subtype reliant on SCFA metabolic reprogramming and M2 macrophage crosstalk. The GAS6-TYRO3 axis and Mmut-mediated methylmalonic acid accumulation represent actionable targets. Combining myeloid-GAS6 ablation with immune checkpoint blockade overcomes therapy resistance, offering a precision strategy for high-risk melanoma.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"279"},"PeriodicalIF":12.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stroma drives axonogenesis and nerve-induced aggressiveness in osteosarcoma.","authors":"Gemma Di Pompo, Thimios A Mitsiadis, Pierfrancesco Pagella, Alessandro Pasquarelli, Giuliano Bettini, Silvia Sabattini, Alberto Righi, Sofia Avnet, Nicola Baldini","doi":"10.1186/s13046-025-03532-2","DOIUrl":"https://doi.org/10.1186/s13046-025-03532-2","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma (OS), the most common primary bone malignancy, is a leading cause of cancer-related mortality in children and adolescents. Besides genomic abnormalities, several features of tumour microenvironment (TME), including cancer-associated mesenchymal stromal cells (MSC), have been recognized to play a key role in OS progression. The pathogenetic function of de novo innervation in TME has been extensively studied in carcinomas but is still an unexplored area of investigation in sarcomas, including OS.</p><p><strong>Methods: </strong>We evaluated nerve infiltration in tissue samples from a small cohort of human OS (n = 5) and from canine OS (n = 11), a translational model for the human disease, by βIII-tubulin immunostaining. We then analysed nerve-stroma-tumour crosstalk using direct and indirect co-cultures of dorsal root ganglion (DRG) neurons with OS/tumour-associated mesenchymal stromal cells (MSC and cancer-associated fibroblasts, CAF), both under standard and microfluidic conditions. In particular, we investigated the effects of tumour and stromal cells on axonal tropism and outgrowth by measuring neurite recruitment, length, and branches and, vice versa, the impact of neuron-derived secretome on OS cell proliferation and migration. Finally, we assessed the secretion of pro-neurotrophic mediators, including brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and nerve growth factor (NGF), by MSC, CAF, and OS cells. The functional roles of IL-6 and BDNF were also verified by the blocking antibody Tocilizumab (TCZ) and the neutralizing Anti-BDNF antibody.</p><p><strong>Results: </strong>We provided evidence of OS innervation within and surrounding the tumour in association with mesenchymal stroma that also corresponded to the most proliferative area of the tumour (Ki-67+). In vitro, both MSC and, to a lesser extent, OS cells promoted axonal growth through cytokine (IL-6) and neuromodulator (BDNF) secretion. Extracellular acidosis - a hallmark of OS aggressiveness - amplified IL-6 release by stromal cells, and its pro-neurogenic effect was prevented by IL-6 blockade. In turn, tumour-associated innervation stimulated OS cell proliferation and migration, eventually driving tumour aggressiveness.</p><p><strong>Conclusions: </strong>We showed, for the first time, that bone-associated nerves, fostered by the OS microenvironment, promote tumour aggressiveness. Interfering with the nerve-tumour axis, particularly with the signalling associated with mesenchymal stroma, offers novel opportunities for OS treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"276"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-423-5p is a metabolic and growth tuner in hepatocellular carcinoma via MALAT-1 and mitochondrial interaction.","authors":"Marco Bocchetti, Alessia Maria Cossu, Manuela Porru, Maria Grazia Ferraro, Carlo Irace, Rossella Tufano, Giovanni Vitale, Gabriella Misso, Nicola Amodio, Marianna Scrima, Ines Simeone, Michele Ceccarelli, Ugo Chianese, Lucia Altucci, Vincenzo Desiderio, Tarik Regad, Michele Caraglia, Silvia Zappavigna","doi":"10.1186/s13046-025-03524-2","DOIUrl":"https://doi.org/10.1186/s13046-025-03524-2","url":null,"abstract":"<p><strong>Background: </strong>MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are key regulators of gene expression and play a crucial role in cancer progression. Recent studies have highlighted miR-423-5p as a potential modulator in hepatocellular carcinoma (HCC), especially in patients responding to sorafenib treatment. A functional interaction with the oncogenic lncRNA MALAT-1 has been hypothesized, suggesting a regulatory mechanism that may influence tumor aggressiveness.</p><p><strong>Methods: </strong>To investigate this interaction, we analyzed in silico patient datasets to correlate miR-423-5p and MALAT-1 expression with overall survival (OS) and disease free survival (DFS). Stable overexpression of miR-423-5p and MALAT-1 was achieved in HCC cell lines (HepG2, Hep3B, and SNU387) using a lentiviral transduction system. Functional assays were performed to assess proliferation, migration, invasion, and clonogenic potential. The interaction between miR-423-5p and MALAT-1 was confirmed by RNA immunoprecipitation (RIP), followed by transcriptomic analysis using next-generation sequencing (NGS). Mitochondrial activity was evaluated using the Seahorse Mito Stress Test to measure oxygen consumption rate (OCR) and ATP production. In vivo experiments in orthotopic mouse models were performed to assess tumor growth.</p><p><strong>Results: </strong>Patient data analysis revealed that high miR-423-5p expression correlated with a less aggressive tumor phenotype and improved survival, while MALAT-1 was associated with poorer prognosis. In vitro, miR-423-5p overexpression reduced MALAT-1 levels and significantly impaired proliferation, migration, and invasion. NGS analysis identified transcriptomic changes linked to tumor progression and metabolic shift. The Seahorse Mito Stress Test demonstrated decreased cellular respiration and ATP production upon miR-423-5p overexpression. In vivo, both tumors derived from miR-423-5p-overexpressing cells and MALAT-1 downregulation by ASO GapmeR evidenced a significantly reduced growth compared to controls.</p><p><strong>Conclusion: </strong>These findings suggest, for the first time, that miR-423-5p acts as a tumor suppressor affecting mitochondrial metabolism through MALAT-1 downregulation in HCC. This regulatory axis represents a potential therapeutic target for precision medicine approaches in liver cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"270"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O-GlcNAcylation of UBAP2L regulates stress granule formation and sunitinib resistance in clear cell renal cell carcinoma.","authors":"Jiajun Xing, Baochao Li, Songbo Wang, Zengjun Wang, Chenkui Miao","doi":"10.1186/s13046-025-03534-0","DOIUrl":"https://doi.org/10.1186/s13046-025-03534-0","url":null,"abstract":"<p><strong>Background: </strong>Sunitinib resistance is one of the main reasons for the poor prognosis of clear renal cell carcinoma (ccRCC). Moreover, Stress granules (SGs) was found to enhance the stress adaptation capability of tumor cells, becoming an important mechanism for drug resistance in various cancers.</p><p><strong>Methods: </strong>We developed sunitinib-resistant patient-derived xenograft (PDX) and organoid (PDO) models to investigate sunitinib resistance in ccRCC. Proteomic analysis identified UBAP2L as a key mediator of this resistance. To explore its role in stress granule formation and sunitinib resistance, we conducted both in vitro and in vivo studies. We further elucidated the regulatory mechanisms of UBAP2L O-GlcNAcylation using immunoprecipitation, mass spectrometry, modification-based proteomics, RNA sequencing (RNA-seq), and RNA immunoprecipitation sequencing (RIP-seq).</p><p><strong>Results: </strong>In this study, enrichment of UBAP2L was elucidated to be significantly associated with sunitinib-resistant ccRCC patient-derived xenograft (PDX) model. Functional experiments showed that UBAP2L protected ccRCC from apoptosis and promoted ccRCC prolifecation and angiogenesis upon sunitinib treatment, thus enhancing drug resistance of ccRCC cells. Furthermore, mechanistic investigation demonstrated that O-GlcNAcylation of UBAP2L promoted its protein stability via inhibiting TRIM37-mediated ubiquitination and it regulated stress granule formation, thereby enhancing the mRNA stability of Melk and activating the PI3K signaling pathways.</p><p><strong>Conclusions: </strong>These results validated the significant roles of O-GlcNAcylation of UBAP2L in ccRCC sunitinib resistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of ccRCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"273"},"PeriodicalIF":12.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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":"https://doi.org/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":"","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":"","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":"https://doi.org/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":"","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":"","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":"https://doi.org/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":"","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":"","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":"https://doi.org/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":"","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":"","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":"https://doi.org/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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}