Molecular Oncology最新文献

{"title":"ZW4864-mediated inhibition of the β-catenin/BCL9/BCL9L complex reveals therapeutic potential in bladder cancer.","authors":"Roland Kotolloshi, Mandy Berndt-Paetz, Eileen Lerner, Gregoire Najjar, Anca Azoitei, Krishna Pal Singh, Shailendra Kumar Gupta, Olaf Wolkenhauer, Cagatay Günes, Otmar Huber, Marc-Oliver Grimm, Daniel Steinbach","doi":"10.1002/1878-0261.70292","DOIUrl":"10.1002/1878-0261.70292","url":null,"abstract":"<p><p>Bladder cancer is the most prevalent malignancy of the urinary tract; nevertheless, its progression and treatment continue to pose substantial challenges. While the molecular mechanisms underlying bladder cancer progression remain unknown, the Wnt/β-catenin signaling pathway has established roles in cancer progression. In this study, we investigated the contribution of BCL9(L) (coactivators of β-catenin) to bladder cancer progression and evaluated the therapeutic potential of disrupting the β-catenin/BCL9(L) complex. We demonstrate that BCL9L exerts oncogenic effects on the proliferation and invasion of bladder cancer cells and the knockdown of BCL9 also reduced the proliferation, migration, and invasion of bladder cancer cells, suggesting similar oncogenic roles. Pharmacological inhibition of the β-catenin/BCL9(L) complex using ZW4864 suppresses a subset of Wnt/β-catenin targets in bladder cancer cells, indicating the inhibition of canonical Wnt signaling. We show ZW4864 has an inhibitory effect on the proliferation, migration, and invasion of bladder cancer cells and impedes the growth and formation of multicellular bladder cancer organoids. These findings demonstrate the crucial role of BCL9 and BCL9L in bladder cancer progression and highlight the β-catenin/BCL9(L) axis as a promising therapeutic target.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2296-2322"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer cell-intrinsic type 1 interferon: production, signaling, and outcomes within sex-biased, female malignancies.","authors":"Ashlyn Conant, Nora Badiner, Sharon Asariah, Kiera McGivney, Vishwa Shah, Tise Suzuki, Yevgeniya J Ioffe, Juli J Unternaehrer","doi":"10.1002/1878-0261.70311","DOIUrl":"10.1002/1878-0261.70311","url":null,"abstract":"<p><p>Type 1 interferons (IFN-1), such as IFN-α and IFN-β, are the most well-studied interferon class due to their abundant expression, widespread signaling, and potent immunomodulatory functions. Although the role of these cytokines in mediating antiviral defense responses and immune activation has been well-studied, recent studies have suggested they play a more nuanced role in directing cell-autonomous responses in cancer. The role of cancer cell-autonomous IFN-1 production and signaling is complex and context dependent. IFN-1 has been shown to participate in both tumor-suppressing and -promoting activities based on the intensity and duration of the IFN-1 signal received. The cell-intrinsic roles appear to be immune-independent, mediating cancer cell responses to traditional therapies and regulating tumor progression. This review aimed to summarize the various roles of IFN-1 in cancer, with a focus on female-related malignancies-including ovarian, breast, cervical, and endometrial cancers-emphasizing the molecular mechanisms surrounding IFN-1 production and signaling, downstream functional outcomes, and therapeutic implications essential to understanding the pro- and antitumor roles of IFN-1.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2135-2162"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13415916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interferon beta drives therapy resistance in a patient-derived model of high-grade serous ovarian cancer.","authors":"Ashlyn Conant, Tise Suzuki, Kiera McGivney, V S S Abhinav Ayyadevara, Sharon Asariah, Jay Deng, Ethan Nyein, Jacqueline Coats, Gary Yu, Yevgeniya J Ioffe, Christian Hurtz, Juli J Unternaehrer","doi":"10.1002/1878-0261.70305","DOIUrl":"10.1002/1878-0261.70305","url":null,"abstract":"<p><p>Type 1 interferon (IFN-1) production and signaling are frequently activated in response to DNA damage and have been associated with the development of therapy resistance in cancer. However, the cell-autonomous role of IFN-1 in driving resistance in high-grade serous ovarian cancer (HGSOC) remains unclear. Specifically, whether IFN-1 functions in HGSOC as solely a response to genotoxic stress due to genotoxic therapy as frontline treatment, or can independently act in driving resistance phenotypes, has not been studied. Utilizing a patient-derived model of cisplatin-sensitive (SE) and -resistant (CR) HGSOC, we demonstrate that chronic cisplatin exposure is associated with enrichment of IFN-1 signaling and an interferon-related DNA damage resistance signature. Acute cisplatin treatment elicited dynamic IFN-1 signaling in both SE and CR cells, indicating a conserved stress response. However, chronic, low-level exposure to exogenous IFNβ, without a DNA-damaging agent, phenocopied several features of chronic cisplatin-driven resistance, including reduced therapeutic sensitivity and decreased proliferation. Together, these findings identify IFNβ as a driver of resistance-associated phenotypes and highlight cell-autonomous IFN-1 signaling as a potential biomarker for resistance and therapeutic target in platinum-resistant disease.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2323-2339"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: Identification of Recurrence-Related MicroRNAs in Hepatocellular Carcinoma Following Liver Transplantation.","authors":"","doi":"10.1002/1878-0261.70313","DOIUrl":"10.1002/1878-0261.70313","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Retraction: &lt;/strong&gt;Z.-B. Han, L. Zhong, M.-J. Teng, J.-W. Fan, H.-M. Tang, J.-Y. Wu, H.-Y. Chen, Z.-W. Wang, G.-Q. Qiu, and Z.-H. Peng, \"Identification of Recurrence-Related MicroRNAs in Hepatocellular Carcinoma following Liver Transplantation,\" Molecular Oncology 6, no. 4 (2012): 445-457, https://doi.org/10.1016/j.molonc.2012.04.001. This article, published online on 17 April 2012 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Kevin Ryan; the Federation of European Biochemical Societies; and John Wiley and Sons Ltd. A third-party organization contacted the publisher regarding concerns pertaining to deceased donor organ sourcing practices in multiple articles, including this one. Credible reporting has been published widely, which indicates that research featuring organ transplantation in China did not comply with international ethics standards. As reported by Rogers et al. and others [1-3], concerns have been raised about the sourcing of organs for transplantation in China during the period relevant to this study, with questions about compliance with internationally accepted ethical standards and transparency in donor procurement practices at the time of publication. The Materials and Methods section for this article indicate that the study reviewed data from liver transplantation patients between January 2002 and December 2007. The article states that the study protocols were approved by the Institutional Review Boards of Shanghai First People's Hospital and Shandong Provincial Qianfoshan Hospital and that informed consent was obtained from patients. No information regarding organ donor sources was provided. Because the entirety of liver transplant cases reported in this article occurred before the existence of a voluntary organ donation program, serious doubts remain regarding the origins of these donations. The authors did not respond to inquiries made by the publisher about these concerns. Furthermore, a third party had reported on PubPeer [4] that the miR-24 and miR-126 graphs in Figure 2A were duplicated despite showing different experimental conditions. Further investigation by the journal editors found that the miR0886-5p and miR-147 graphs in Figure 5A and the miR-147 and miR-223 graphs in Figure 2B contained additional data overlap. Unexpected similarities were also found in portions of the graphs between Figures 3A and 3B and between Figures 4A and 4B. The publisher and editors cannot verify the ethics committee registration or the informed consent protocols for the study reported in this article. Furthermore, questions remain as to whether the organ donations reported in the article complied with internationally recognized ethical guidelines in place at the time of publication. Lastly, evidence of data duplication and manipulation compromises the editors' confidence in the results presented in this article. Therefore, the journal has decided to issue","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2382-2383"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13458513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: NNK From Tobacco Smoking Enhances Pancreatic Cancer Cell Stemness and Chemoresistance by Creating a β2AR-Akt Feedback Loop That Activates Autophagy.","authors":"","doi":"10.1002/1878-0261.70312","DOIUrl":"10.1002/1878-0261.70312","url":null,"abstract":"<p><strong>Retraction: </strong>X. Chen, W. Zhang, R. Liu, Z. Zhu, M. Gong, Q. Wang, W. Qian, Z. Wu, Q. Ma and Z. Wang, \"NNK From Tobacco Smoking Enhances Pancreatic Cancer Cell Stemness and Chemoresistance by Creating a β2AR-Akt Feedback Loop That Activates Autophagy,\" Molecular Oncology 16, no. 15 (2022): 2881-2895, https://doi.org/10.1002/1878-0261.13230. The above article, published online on 20 May 2022 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor-in-Chief, Kevin Ryan; FEBS Press; and John Wiley and Sons Ltd. The retraction has been agreed following concerns raised by a third party. An investigation identified duplication between Figure 5F of this article and a figure published earlier in another article by a different author group. The authors explained that the image was used as reference material and mistakenly incorporated into the figure. The authors provided some supporting data, but this did not meet the criteria for raw data. Given the image duplication and the lack of appropriate raw data, the editors consider the results to be unreliable.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2385"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13399044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148536491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Keratin 19 as a prognostic marker and contributing factor of metastasis and chemoresistance in high-grade serous ovarian cancer.","authors":"Sophia Bielesch, Isabel Vogel, Sina Nokodian, Johanna Moeller, Antonia Blechschmidt, Vicky Hecht, Vanessa Kuentzel, Katharina Thiedig, Melissa Schwab, Oliver Schilling, Holger Bronger, Marion Kiechle, Viktor Magdolen, Tobias Dreyer","doi":"10.1002/1878-0261.70227","DOIUrl":"10.1002/1878-0261.70227","url":null,"abstract":"<p><p>High-grade serous ovarian cancer (HGSOC) is the most prevalent and lethal subtype of epithelial ovarian cancer (EOC), characterised by extensive peritoneal metastasis. The intermediate filament keratin 19 (KRT19) has been linked to tumour progression and chemoresistance in various cancers. However, its role varies across tumour types and remains unclear for HGSOC. We evaluated KRT19 protein expression in 199 HGSOC patients and correlated findings with clinical outcomes. In vitro, we assessed the effects of KRT19 on tumour-associated mechanisms, including proliferation, migration, adhesion, and spheroid formation. A xenograft mouse model was used to assess tumour burden in vivo. Publicly available datasets enabled in silico validation. KRT19 was significantly overexpressed in HGSOC, and high expression was associated with reduced overall survival. In vivo, KRT19-overexpression increased peritoneal tumour burden. In vitro and ex vivo, KRT19 induced a hybrid epithelial phenotype through enhanced epithelial-mesenchymal plasticity (EMP), promoting adhesion, migration, and spheroid integrity, thereby potentially supporting metastatic processes. Further, KRT19 could contribute to paclitaxel resistance. Altogether, KRT19 represents a potential independent prognostic marker and therapeutic target to inhibit metastatic dissemination.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2243-2261"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13399148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimethyl fumarate combined with cisplatin at subcytotoxic doses sensitizes cervical cancer toward ferroptosis and apoptosis through GSH restriction and p53 (re)activation.","authors":"Carolina Punziano, Giuseppina Minopoli, Simona Romano, Laura Marrone, Katia Aquilano, Maria Lina Tornesello, Raffaella Faraonio","doi":"10.1002/1878-0261.70216","DOIUrl":"10.1002/1878-0261.70216","url":null,"abstract":"<p><p>Cervical cancer is one of the leading causes of tumor-related deaths among women. Chemotherapy in cervical cancer is mainly based on cisplatin, but this drug has limited efficacy; therefore, alternative treatment options are needed. Ferroptosis represents a novel form of cell death. In cervical epithelium, ferroptosis occurs in the early neoplastic stages of papillomavirus infection but shifts to evasion in carcinoma. Combination therapy has the potential to enhance cancer cell death and overcome resistance development. Herein we demonstrate that dimethyl fumarate (DMF), a Food and Drug Administration (FDA)-approved anti-inflammatory drug, induces ferroptosis in cervical cancer cells in a dose-dependent manner and inhibits growth in spheroid models. Cotreatment with DMF and cisplatin significantly decreases cell viability compared to either drug alone. Under DMF/cisplatin combination, cervical cancer cells underwent to glutathione depletion and p53 (re)activation, leading to cell death by both ferroptosis and apoptosis. We found a p53-mediated downregulation of the Solute Carrier Family 7 Member 11 (SLC7A11)/Cystine/Glutamate Transporter (xCT) expression and glutathione levels. Our results suggest that combined administration of DMF and cisplatin, by targeting the dependency of cervical cancer cells on glutathione and (re)activating p53, represents a promising anticancer therapeutic strategy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2356-2381"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of a humanized patient-derived xenograft mouse model of high-grade serous ovarian cancer for preclinical evaluation of combination immunotherapy.","authors":"Luka Tandaric, Line Bjørge, Martine Rott Lode, Cecilie Fredvik Torkildsen, Pia Aehnlich, Rammah Elnour, Daniela Elena Costea, Lars Andreas Akslen, Liv Cecilie Vestrheim Thomsen, Emmet McCormack, Katrin Kleinmanns","doi":"10.1002/1878-0261.70231","DOIUrl":"10.1002/1878-0261.70231","url":null,"abstract":"<p><p>The limited efficacy of immunotherapy in clinical trials in high-grade serous ovarian cancer (HGSOC) may improve by implementing experimental models that are more reflective of human biology into preclinical studies. To address this, we developed and validated a humanized patient-derived xenograft mouse model of HGSOC. Human hematopoietic stem cells and patient-derived HGSOC cells were engrafted into immunodeficient mice. The mice were administered durvalumab (anti-PD-L1) and/or oleclumab (anti-CD73) immunotherapy intraperitoneally twice a week for 5 weeks. The treatment showed good tolerability with no observed side effects, though it failed to elicit a measurable antitumor response. Leukocytes in primary tumors were analyzed immunohistochemically, and circulating T cells were characterized using spectral flow cytometry. All tumors exhibited an immune-excluded immunophenotype. No significant inter-group differences in disease burden, intratumoral leukocyte density, or circulating T cells were observed. In the durvalumab-only group, tumor burden significantly positively correlated with intratumoral cytotoxic and regulatory T-cell densities. This model reflects the immunotherapy resistance of human disease in line with clinical findings, providing a robust platform for studying tumor-immune interactions and immunosuppressive mechanisms in HGSOC. Impact statement Our results address the critical need for representative preclinical models for testing combination immunotherapy in HGSOC by providing a robust preclinical platform that can enhance the reliability of preclinical data and contribute to the improvement of the design and outcomes of future clinical trials.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2203-2219"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147458764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal circulating tumor DNA profiling in patients with advanced endometrial cancer using an off-the-shelf targeted NGS panel.","authors":"Carlos Casas-Arozamena, Karin Teien Lande, Eva Diaz, Ana Vilar, Juan Cueva, Efigenia Arias, Victoria Sampayo, Alicia Abalo, Nerea González, Eva Colás, Antonio Gil-Moreno, Miguel Abal, Gema Moreno-Bueno, Therese Sørlie, Kristina Lindemann, Laura Muinelo-Romay","doi":"10.1002/1878-0261.70246","DOIUrl":"10.1002/1878-0261.70246","url":null,"abstract":"<p><p>Intratumor heterogeneity presents a major challenge in precision oncology for endometrial cancer (EC). Circulating tumor DNA (ctDNA) offers a minimally invasive method to monitor tumor evolution and therapeutic resistance. In this retrospective study, we evaluated a tumor-agnostic NGS panel to detect and track ctDNA in 18 EC patients and directly compared its performance with a tumor-informed ddPCR approach. ctDNA was detected by NGS in over 60% of plasma samples, while ddPCR showed higher positivity rates in paired samples (71.9% vs 62.5%), with overall concordance of 65.7% and fair agreement (Cohen's kappa = 0.23). The cfDNA-NGS panel identified a broad spectrum of alterations, including relapse-specific mutations indicative of clonal evolution, but showed lower sensitivity for low-frequency variants compared with ddPCR. Discordant cases, including false-negative results in both approaches, highlight the impact of assay sensitivity, target selection, and biological factors on ctDNA detection. ctDNA dynamics correlated with disease progression and treatment response, although detection was limited in cases with brain metastases. These findings support the utility of tumor-agnostic ctDNA monitoring in advanced EC and highlight the importance of assay quality and careful interpretation to address limitations such as clonal hematopoiesis and technical sensitivity.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2188-2202"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered extracellular vesicles enriched with the miR-214/199a cluster enhance the efficacy of chemotherapy in ovarian cancer.","authors":"Weida Wang, Ayesha Alvero, Yi Qin, Mingjin Wang, Alexandra Fox, Yanfeng Li, Michael Millman, Amy Kemper, Gil Mor, Xian Shuang Liu, Michael Chopp, Zheng Gang Zhang, Yi Zhang","doi":"10.1002/1878-0261.70224","DOIUrl":"10.1002/1878-0261.70224","url":null,"abstract":"<p><p>Recurrent ovarian cancer (OC) remains a major cause of mortality due to chemoresistance and metastasis. Epigenetic aberrations, particularly dysregulated microRNA (miRNA) expression, contribute to disease progression and represent a promising therapeutic target. Here, we identify the miR-214-3p/miR-199a-5p cluster as a stage-associated, tumor-suppressive network that is lost in recurrent and chemoresistant OC but can be elevated using engineered small extracellular vesicles enriched with this miRNA cluster (m214-sEVs). Using a clinically relevant mouse model that recapitulates spontaneous OC relapse following platinum-based chemotherapy, we show that m214-sEVs are internalized by OC cells and niche fibroblasts, leading to increased intracellular levels of this cluster and suppression of key chemoresistance-associated pathways, including through downregulation of Toll-like receptor 4 (TLR4), β-catenin, and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein YKT6. m214-sEV treatment reprograms secondary tumor-derived sEVs toward a less prometastatic cargo profile and decreases carboplatin resistance and cell migration. Enforced YKT6 overexpression abrogates these effects, establishing YKT6 as a key downstream effector. Collectively, these findings support engineered sEVs as a translatable strategy to overcome chemoresistance and disrupt pro-tumorigenic EV signaling in recurrent OC.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2220-2242"},"PeriodicalIF":4.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13398902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}