Molecular Cancer最新文献

{"title":"Correction: Proteogenomic characterization of molecular and cellular targets for treatment‑resistant subtypes in locally advanced cervical cancers","authors":"Do Young Hyeon, Dowoon Nam, Hye‑Jin Shin, Juhee Jeong, Eunsoo Jung, Soo Young Cho, Dong Hoon Shin, Ja‑Lok Ku, Hye Jung Baek, Chong Woo Yoo, Eun‑Kyung Hong, Myong Cheol Lim, Sang‑Jin Lee, Young‑Ki Bae, Jong Kwang Kim, Jingi Bae, Wonyoung Choi, Su‑Jin Kim, Seunghoon Back, Chaewon Kang, Inamul Hasan Madar, Hokeun Kim, Suhwan Kim, Duk Ki Kim, Jihyung Kang, Geon Woo Park, Ki Seok Park, Yourae Shin, Sang Soo Kim, Keehoon Jung, Daehee Hwang, Sang‑Won Lee, Joo‑Young Kim","doi":"10.1186/s12943-025-02373-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02373-z","url":null,"abstract":"<p><b>Correction: Mol Cancer 24</b>,<b> 77 (2025)</b></p><p><b>https://doi.org/10.1186/s12943-025-02256-3</b></p><p>Following the publication of the original article [1], the authors, during their post-publication review, have noted that the standard acknowledgment required by the International Cancer Proteogenome Consortium (ICPC) was inadvertently omitted. Because the study was conducted under the auspices of ICPC, inclusion of this language is essential for proper attribution and for the consortium’s ongoing efforts to catalogue and promote ICPC-supported research. They therefore respectfully request the publication of an article correction note to address the change in Acknowledgements section. The incorrect and correct Acknowledgements are provided below.</p><p> Incorrect Acknowledgements:</p><p>This work was supported by grants from the Proteogenomic Research Project of National Cancer Center, Korea (NCC-1810861, NCC-1810862, NCC-1711260, NCC-2210490), the Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education, Korea.</p><p>(2018R1D1A1A09084250, 2021R1F1A1052407, RS-2023-00208004, RS-2023-00217571), and the NAVER Corporation (Grant No. 3720230110). This work was also supported by the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC) grant funded by the Korean government (Ministry of Education) (2019R1A6C1010028) and by the NRF funded by the Korean government (Ministry of Science and ICT) (NRF-2022M3H9A2086450).</p><p> Correct Acknowledgements:</p><p>This work was supported by grants from the Proteogenomic Research Project of National Cancer Center, Korea (NCC-1810861, NCC-1810862, NCC-1711260, NCC-2210490), the Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education, Korea (2018R1D1A1A09084250, 2021R1F1A1052407, RS-2023-00208004, RS-2023-00217571), and the NAVER Corporation (Grant No. 3720230110). This work was also supported by the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC) grant funded by the Korean government (Ministry of Education) (2019R1A6C1010028) and by the NRF funded by the Korean government (Ministry of Science and ICT) (NRF-2022M3H9A2086450). This work was done under the auspices of a Memorandum of Understanding between Korea University and the U.S. National Cancer Institute’s International Cancer Proteogenome Consortium (ICPC). ICPC encourages international cooperation among institutions and nations in proteogenomic cancer research in which proteogenomic datasets are made available to the public. This work was also done in collaboration with the U.S. National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC).</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Hyeon DY, Nam D, Shin HJ, et al. Proteogenomic characterization of molecula","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"11 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260175","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":"Wnt/β-catenin mediated signaling pathways in cancer: recent advances, and applications in cancer therapy","authors":"Xiuzhu Wu, Haiying Que, Qingfang Li, Xiawei Wei","doi":"10.1186/s12943-025-02363-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02363-1","url":null,"abstract":"The Wnt/β-catenin signaling pathway is a highly conserved signaling pathway closely linked to cancer development through various biological processes, including oncogenic transformation, genomic instability, cancer cell proliferation, stemness, metabolism, cell death, immune regulation, and metastasis. Notably, its activation plays a crucial role in drug resistance to chemotherapy, targeted therapy and immunotherapy. Recent advances in drug development have identified several targeted inhibitors acting at key nodal points of this pathway, with some demonstrating synergistic efficacy when combined with immunotherapeutic agents. This review provides a comprehensive analysis of current understanding regarding the Wnt/β-catenin pathway in malignancy, emphasizing its multifaceted roles in tumor initiation, therapeutic resistance, and immune regulation. Additionally, we summarized the clinical performance of combination therapies targeting the Wnt/β-catenin pathway in conjunction with chemotherapy, targeted therapy, and immunotherapy. Although clinical development remains at a relatively early stage, pharmacological modulation of Wnt/β-catenin signaling offers considerable potential as a novel therapeutic paradigm in precision oncology.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"58 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252010","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":"Differential susceptibility and role for senescence in CART cells based on costimulatory domains","authors":"Ismail Can, Elizabeth L. Siegler, Olivia L. Sirpilla, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Jennifer M. Feigin, Makena L. Rodriguez, Omar L. Gutierrez-Ruiz, Ekene J. Ogbodo, Truc N. Huynh, Brooke L. Kimball, Long K. Mai, Mehrdad Hefazi, Lionel Kankeu Fonkoua, Hong Xia, Imene Hamaidi, Berke Alkan, Fatih Sezer, H. Atakan Ekiz, R. Leo Sakemura, Saad S. Kenderian","doi":"10.1186/s12943-025-02371-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02371-1","url":null,"abstract":"Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods. Using CD19-targeted CART cells with costimulation via 4-1BB-CD3ζ (BBζ) or CD28-CD3ζ (28ζ), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BBζ. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BBζ activity but improved 28ζ activity in preclinical studies. These findings were supported by analyses of independent patient data sets; senescence signatures in CART cell products were associated with non-response to BBζ but with improved clinical outcomes in 28ζ treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART cells. We identified senescence as a cause of failure in CART cell therapy, predominantly in 4-1BB-costimulated CART cells.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252009","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":"CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation","authors":"Jianghua Li, Lu Xu, Jiayu Wang, Xuning Wang, Yuting Lin, Alex Yutian Zou, Fangli Ren, Yinyin Wang, Jun Li, Zhijie Chang","doi":"10.1186/s12943-025-02361-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02361-3","url":null,"abstract":"Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC. • Somatic CREPT gene copy-number amplifications with elevated expression occur in the metastatic triple-negative breast cancer (TNBC) and correlate with poor patient survival • CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops • CREPT-mediated co-operational chromatin loops regulate metastatic genes during the metastasis of TNBC • Depleting CREPT by adeno-associated virus (AAV) blocks TNBC metastasis in preventative and therapeutic mouse models","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 6 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252011","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":"The tumor microenvironment in hepatocellular carcinoma: mechanistic insights and therapeutic potential of traditional Chinese medicine","authors":"Xiaojun Su, Xiuli Yan, Hui Zhang","doi":"10.1186/s12943-025-02378-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02378-8","url":null,"abstract":"Hepatocellular carcinoma (HCC) progression and therapeutic resistance are profoundly influenced by the dynamic interplay within the tumor microenvironment (TME). The HCC TME comprises a complex network of cellular components, including cancer-associated fibroblasts, tumor-associated macrophages, and infiltrating immune cells, alongside non-cellular factors such as extracellular matrix proteins, cytokines, and angiogenic mediators. These elements collectively promote immune evasion, stromal remodeling, and neovascularization, driving tumor aggressiveness and treatment resistance. Emerging evidence suggests that traditional Chinese medicine (TCM) may offer a promising strategy to reprogram the immunosuppressive HCC TME through multimodal mechanisms, such as immunomodulation to enhance anti-tumor immunity and deplete regulatory cell populations, stromal normalization to attenuate fibroblast activation and pathological matrix deposition, and anti-angiogenic effects to restrict tumor vascularization. Notably, TCM compounds exhibit synergistic potential when combined with conventional therapies, including immune checkpoint inhibitors, tyrosine kinase inhibitors, and cytotoxic regimens, potentially enhancing efficacy while mitigating adverse effects. However, key challenges persist, such as intratumoral heterogeneity, pharmacokinetic variability of herbal formulations, and the need for rigorous preclinical-to-clinical translation. Future investigations should prioritize systems-level dissection of TCM-mediated TME modulation using omics technologies, rational design of TCM-based combination therapies guided by mechanistic studies, and standardization of clinically translatable TCM regimens. This review synthesizes current understanding of TME-driven HCC pathogenesis and highlights the emerging paradigm of TCM as a complementary modality to recalibrate the tumor-immune-stroma axis for improved therapeutic outcomes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"18 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252008","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":"Nanomedicine in Cancer Therapeutics: Current Perspectives from Bench to Bedside","authors":"K. M. Abdullah, Gunjan Sharma, Ajay P. Singh, Jawed A. Siddiqui","doi":"10.1186/s12943-025-02368-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02368-w","url":null,"abstract":"Cancer is among the leading causes of death worldwide, with projections indicating that it will claim 35 million lives by the year 2050. Conventional therapies, such as chemotherapy and immune modulation, have reduced cancer mortality to some extent; however, they have limited efficacy due to their broad mode of action, often resulting in cytotoxic effects on normal cells along with the malignant tissues, ultimately limiting their overall optimal therapeutic efficacy outcomes. Rapid advances in nanotechnology and an evolving understanding of cancer mechanisms have propelled the development of a diverse array of nanocarriers to vanquish the hurdles in achieving sophisticated drug delivery with reduced off-target toxicity. Nanoformulations can deliver the anti-cancer agents precisely to the tumor cell by integrating a multitarget approach that allows for tissue-, cell-, or organelle-specific delivery and internalization. Despite the immense interest and unmatched advancements in modern oncology equipped with nanomedicines, only a few nanoformulations have successfully translated into clinical settings. A major reason behind this shortcoming is the lack of a rationale design incorporating smart, responsive targeting features, leading to a compromised therapeutic window due to inefficient internalization or erroneous intracellular localization with unsuccessful payload release. This review aims to summarize the recent perspective of nanomedicine and its translation to clinical practice, with a particular focus on the evolution of strategies used in tumor targeting from traditional EPR-based passive mechanisms to advanced active and multi-stage approaches. We highlight the coupling of organelle-specific and stimuli-responsive nanocarriers, discuss the potential of biomimetic and cell-mediated delivery systems, and also shed light on technologies such as microfluidics, tumor-on-chip models, and AI-assisted synthesis. Finally, this review explores translational hurdles ranging from biological and manufacturing challenges to regulatory bottlenecks and outlines how innovative modeling systems and engineering solutions can bridge the gap from bench to bedside in cancer nanotherapeutics.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"6 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144238102","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":"Targeting PERP promotes anti-tumor immunity in HNSCC by regulating tumor immune microenvironment and metabolic homeostasis","authors":"Xueying Wang, Yuxi Tian, Xiaohong Wu, Yewen Zhu, Huihong Chen, Zeyao Wang, Zihan Liu, Jiaqi Tan, Zhaoyu Pan, Jiaoyan Cao, Zhenjiang Li, Xin Zhang, Zhongjie Shi, Juncheng Wang, Tong Liu","doi":"10.1186/s12943-025-02360-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02360-4","url":null,"abstract":"PERP may have the potential to function as an oncogene. However, the precise function, prognostic value, and predictive significance remain shrouded in ambiguity. We conducted an in-depth analysis using pan-cancer RNA sequencing data and various online web tools to investigate the correlation between PERP and crucial clinical outcomes such as prognosis, tumor microenvironment, and tumor metabolism. In addition, we explored the tumor-promoting role of PERP and its potential mechanisms through models such as immunofluorescence staining, flow cytometry, cell proliferation assays, wound healing assays, cell migration assays, mass spectrometry analysis and isotope tracing. Further in vivo models confirmed the functional consistency of PERP across pan-cancer. Finally, we analyzed the potential of PERP as a predictive factor for immunotherapy sensitivity in a clinical cohort. PERP exhibits elevated expression in the majority of cancer types and impedes immune cell infiltration as well as immune checkpoint reactivity in pan-cancer. We confirmed that PERP can promote tumor progression by tumor cell proliferation, scratch and transwell experiments. Meanwhile, the absence of PERP restricts the flux of 13C6-glucose into glycolysis and the tricarboxylic acid (TCA) cycle. Importantly, the deficiency of PERP enhances the in vivo anti-tumor efficacy of PD1 monoclonal antibodies. In addition, low PERP expression is highly correlated with the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy. PERP represents a promising predictive/diagnostic biomarker and therapeutic target for HNSCC patients.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"51 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236975","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":"Epithelial-to-mesenchymal transition (EMT) and cancer metastasis: the status quo of methods and experimental models 2025","authors":"Heike Allgayer, Samikshya Mahapatra, Barnalee Mishra, Biswajit Swain, Suryendu Saha, Sinjan Khanra, Kavita Kumari, Venketesh K. Panda, Diksha Malhotra, Nitin S. Patil, Jörg H. Leupold, Gopal C. Kundu","doi":"10.1186/s12943-025-02338-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02338-2","url":null,"abstract":"Epithelial-to-mesenchymal transition (EMT) is a crucial cellular process for embryogenesis, wound healing, and cancer progression. It involves a shift in cell interactions, leading to the detachment of epithelial cells and activation of gene programs promoting a mesenchymal state. EMT plays a significant role in cancer metastasis triggering tumor initiation and stemness, and activates metastatic cascades resulting in resistance to therapy. Moreover, reversal of EMT contributes to the formation of metastatic lesions. Metastasis still needs to be better understood functionally in its major but complex steps of migration, invasion, intravasation, dissemination, which contributes to the establishment of minimal residual disease (MRD), extravasation, and successful seeding and growth of metastatic lesions at microenvironmentally heterogeneous sites. Therefore, the current review article intends to present, and discuss comprehensively, the status quo of experimental models able to investigate EMT and metastasis in vitro and in vivo, for researchers planning to enter the field. We emphasize various methods to understand EMT function and the major steps of metastasis, including diverse migration, invasion and matrix degradation assays, microfluidics, 3D co-culture models, spheroids, organoids, or latest spatial and imaging methods to analyze complex compartments. In vivo models such as the chorionallantoic membrane (CAM) assay, cell line-derived and patient-derived xenografts, syngeneic, genetically modified, and humanized mice, are presented as a promising arsenal of tools to analyze intravasation, site specific metastasis, and treatment response. Furthermore, we give a brief overview on methods detecting dissemination and MRD in carcinomas, highlighting its significance in tracking the course of disease and response to treatment. Enhanced lineage tracking tools, dynamic in vivo imaging, and therapeutically useful in vivo models as powerful preclinical tools may still better reveal functional interdependencies between metastasis and EMT. Future directions are discussed in light of emerging views on the biology, diagnosis, and treatment of EMT and metastasis.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"21 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237058","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":"Exosomes in cancer nanomedicine: biotechnological advancements and innovations","authors":"Jacky J. J. Liu, Duanrui Liu, Sally K. Y. To, Alice S. T. Wong","doi":"10.1186/s12943-025-02372-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02372-0","url":null,"abstract":"​​Exosomes, as natural intercellular messengers, are gaining prominence as delivery vehicles in nanomedicine, offering a superior alternative to conventional synthetic nanoparticles for cancer therapeutics. Unlike lipid, polymer, or metallic nanoparticles, which often face challenges related to immunogenicity, targeting precision, and off-tumor toxicity, exosomes can effectively encapsulate a diverse range of therapeutic agents while exhibiting low toxicity, favorable pharmacokinetics, and organotropic properties. This review examines recent advancements in exosome bioengineering over the past decade. Innovations such as microfluidics-based platforms, nanoporation, fusogenic hybrids, and genetic engineering have significantly improved loading efficiencies, production scalability, and pharmacokinetics of exosomes. These advancements facilitate tumor-specific cargo delivery, resulting in substantial improvements in retention and efficacy essential for clinical success. Moreover, enhanced biodistribution, targeting, and bioavailability—through strategies such as cell selection, surface modifications, membrane composition alterations, and biomaterial integration—suggests a promising future for exosomes as an ideal nanomedicine delivery platform. We also highlight the translational impact of these strategies through emerging clinical trials. Additionally, we outline a framework for clinical translation that focuses on: cargo selection, organotropic cell sourcing, precision loading methodologies, and route-specific delivery optimization. In summary, this review emphasizes the potential of exosomes to overcome the pharmacokinetic and safety challenges that have long impeded oncology drug development, thus enabling safer and more effective cancer treatments.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"478 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236977","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":"The EGR1-mediated lncRNA TENM3-AS1 potentiates gastric cancer metastasis via reprogramming fatty acid metabolism","authors":"Yuhui Tang, Baiwei Zhao, Wanchuan Wang, Haoming Chen, Junsheng Zhang, Yi Xie, Yongming Chen, Feizhi Lin, Yuanfang Li, Xiaohui Zhai, Wen Zhou","doi":"10.1186/s12943-025-02341-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02341-7","url":null,"abstract":"Long non-coding RNAs (lncRNAs) are essential modulators in tumor progression. While fatty acid (FA) metabolism can potentiate tumorigenesis, colonization, and metastasis, the roles of lncRNAs in reprograming FA metabolism and regulating gastric cancer (GC) metastasis remain elusive. Whole RNA-sequencing and in silico analyses were conducted to identify clinically significant lncRNAs involved in GC metastasis. Among the identified lncRNAs, we focused on the novel lncRNA TENM3-AS1. RT-qPCR and FISH analyses revealed an increased expression of TENM3-AS1 in GC cell lines and patients. In vitro and in vivo functional experiments validated the effects of TENM3-AS1 to GC metastasis and the reprogramming of FA metabolism. ChIP, Biotinylated RNA pull-down, RIP, CHX-chase assay, ubiquitination assay, and RNA stabilization assay were employed to perceive the mechanisms underlying the effects of TENM3-AS1 in GC cells. TENM3-AS1 expression was significantly elevated in metastatic tumors and advanced primary tumors of GC patients. This increased expression was also associated with a worsened overall survival and progression-free survival. Functionally, TENM3-AS1 enhanced the migration and invasiveness of GC cells in vitro, promoted tumorigenesis and liver metastasis in vivo, and increased FA biosynthesis in GC cells. Mechanistically, our studies showed that the transcription factor EGR1 activated TENM3-AS1, which in turn upregulated the expression of FASN and hnRNPK. Furthermore, TENM3-AS1 interacted with and stabilized hnRNPK by increasing its deubiquitination. This interaction reprogrammed FA metabolism and promoted GC progression by increasing FASN mRNA stability through hnRNPK. In this study, by comparing lncRNA sequencing data from paired primary and peritoneal metastatic tumors and public transcriptome data from non-metastatic and metastatic samples, we clarified a novel lncRNA, TENM3-AS1. It was found that TENM3-AS1 was aberrantly activated in metastatic and advanced primary tumors, and was strongly correlated with a shorter survival in GC patients. Our study reveals the EGR1/TENM3-AS1/ hnRNPK/FASN axis as a novel curative target in metastatic GC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"138 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228828","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}