Journal of Experimental & Clinical Cancer Research最新文献

{"title":"C-FOS promotes the formation of neutrophil extracellular traps and the recruitment of neutrophils in lung metastasis of triple-negative breast cancer.","authors":"Shuai Yan, Wenxi Zhao, Juntong Du, Lizhi Teng, Tong Yu, Peng Xu, Jiangnan Liu, Ru Yang, Yuhan Dong, Hongyue Wang, Lingran Lu, Weiyang Tao","doi":"10.1186/s13046-025-03370-2","DOIUrl":"10.1186/s13046-025-03370-2","url":null,"abstract":"<p><strong>Background: </strong>Neutrophil extracellular traps (NETs) are composed of DNA chains from neutrophils and associated proteolytic enzymes, which play an important role in cancer metastasis. However, the molecular mechanism of NET-mediated lung metastasis in triple-negative breast cancer (TNBC) remains unclear.</p><p><strong>Methods: </strong>The expression levels of NETs in breast cancer specimens and serum were analyzed and compared with normal samples. Single-cell sequencing bioinformatics analysis was conducted to identify differentially expressed genes and functional enrichment related to NET formation in patients with breast cancer. The effects of c-FOS on neutrophil recruitment and NET formation in TNBC were investigated. The upstream and downstream regulatory mechanisms mediated by c-FOS were explored through in vitro and in vivo experiments. Therapeutic approaches targeting c-FOS for treating TNBC were further studied.</p><p><strong>Results: </strong>Inhibition of c-FOS can suppress tumor growth and lung metastasis in TNBC. Mechanistically, c-FOS promotes transcription by binding to the PAD4 promoter region, facilitating the formation of NETs. Additionally, the activation of the ROS-p38 pathway further enhances c-FOS expression. High expression of c-FOS also promotes the expression of inflammatory factors, facilitating neutrophil recruitment. Both in vitro and in vivo experiments demonstrated that the application of T5224 effectively inhibits the formation of NETs, suppressing lung metastasis and tumor growth.</p><p><strong>Conclusion: </strong>In summary, this study demonstrates that the ROS-p38-cFOS-PAD4 axis can increase NET formation in TNBC and promote the expression of inflammatory factors, facilitating neutrophil recruitment. Therefore, targeting this pathway may help inform new therapeutic strategies and provide new insights for immunotherapy in TNBC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"108"},"PeriodicalIF":11.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732660","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":"RASON promotes KRAS^G12C-driven tumor progression and immune evasion in non-small cell lung cancer.","authors":"Jianzhuang Wu, Kexin Xie, Yixuan Zhang, Weiyi Zhang, Rongjie Cheng, Yaliang Zhang, Yugui Xia, Tongyan Liu, Rong Yin, Yudong Qiu, Tao Xu, Rutian Li, Qi Sun, Chao Yan","doi":"10.1186/s13046-025-03369-9","DOIUrl":"10.1186/s13046-025-03369-9","url":null,"abstract":"<p><strong>Background: </strong>KRAS is the most frequently mutated oncogene in human cancers, with KRAS^G12C being a prevalent driver mutation in 12-13% non-small cell lung cancer (NSCLC) cases. Despite breakthroughs in KRAS^G12C inhibitors such as sotorasib (AMG-510) and adagrasib (MRTX-849), clinical resistance remains a challenging issue, highlighting the need for deeper understanding of the molecular mechanisms underlying KRAS^G12C-driven oncogenic signaling in NSCLC. Previously, we identified RASON as a novel regulator of KRAS^G12D/V signaling in pancreatic cancer. Herein, we aim to explore the role of RASON in KRAS^G12C-driven NSCLC and its therapeutic potential.</p><p><strong>Methods: </strong>Immunohistochemistry analysis of NSCLC patient cohorts was performed to demonstrate the correlation between RASON expression and NSCLC progression. Immunoblotting was performed to evaluate the effects of RASON on KRAS^G12C downstream signaling. In vitro and in vivo assays including cell proliferation, sphere formation, tumor implantation and genetic mouse models were performed to determine the oncogenic role of RASON. RNA-seq analysis was utilized to identify the key signaling pathway regulated by RASON. Immunofluorescence, immunoprecipitation, nuclear magnetic resonance and biochemistry assays were used to validate the interaction between KRAS^G12C and RASON. Phagocytosis assay and flow cytometry were conducted to explore the effects of RASON on the tumor immune microenvironment. Pharmacological inhibition in subcutaneous xenograft model was used to determine the therapeutical potential of RASON.</p><p><strong>Results: </strong>RASON is overexpressed in NSCLC with KRAS^G12C mutation and correlates with poor patient prognosis. Genetic knockout of RASON significantly reduced lung tumor burden in LSL-KRAS^G12D; Trp53^R172H/+ mice. In KRAS^G12C-mutant lung cancer cell lines, RASON overexpression enhanced, while CRISPR-mediated knockout suppressed, both in vitro proliferation and in vivo tumor growth. Mechanistically, RASON directly binds KRAS^G12C, stabilizes it in the GTP-bound hyperactive state and promotes downstream signaling. RASON knockout significantly reduced CD47 expression, enhancing macrophage-mediated phagocytosis and anti-tumor immunity. Therapeutically, antisense oligonucleotides targeting RASON not only exhibited tumor-suppressive effects, but also synergized with the KRAS^G12C inhibitor AMG-510 to significantly enhance anti-tumor efficacy.</p><p><strong>Conclusion: </strong>This study reveals RASON as a key oncogenic regulator of KRAS^G12C signaling, driving lung tumorigenesis and progression, and identifies RASON as a promising therapeutic target for KRAS^G12C mutant non-small cell lung cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"106"},"PeriodicalIF":11.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702078","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":"Innovative dual-gene delivery platform using miR-124 and PD-1 via umbilical cord mesenchymal stem cells and exosome for glioblastoma therapy.","authors":"Po-Fu Yueh, I-Tsang Chiang, Yueh-Shan Weng, Yu-Chang Liu, Raymond C B Wong, Cheng-Yu Chen, Justin Bo-Kai Hsu, Long-Bin Jeng, Woei-Cherng Shyu, Fei-Ting Hsu","doi":"10.1186/s13046-025-03336-4","DOIUrl":"10.1186/s13046-025-03336-4","url":null,"abstract":"<p><p>Addressing the challenges of identifying suitable targets and effective delivery strategies is critical in pursuing therapeutic solutions for glioblastoma (GBM). This study focuses on the therapeutic potential of microRNA-124 (miR-124), known for its tumor-suppressing properties, by investigating its ability to target key oncogenic pathways in GBM. The results reveal that CDK4 and CDK6-cyclin-dependent kinases that promote cell cycle progression-are significantly overexpressed in GBM brain samples, underscoring their role in tumor proliferation and identifying them as critical targets for miR-124 intervention. However, delivering miRNA-based therapies remains a major obstacle due to the instability of RNA molecules and the difficulty in achieving targeted, efficient delivery. To address these issues, this research introduces an innovative, non-viral dual-gene delivery platform that utilizes umbilical cord mesenchymal stem cells (UMSCs) and their exosomes to transport miR-124 and programmed cell death protein-1 (PD-1). The efficacy of this dual-gene delivery system was validated using an orthotopic GBM model, which closely mimics the tumor microenvironment seen in patients. Experimental results demonstrate that the UMSC/miR-124-PD-1 complex and its exosomes successfully induce apoptosis in GBM cells, significantly inhibiting tumor growth. Notably, these treatments show minimal cytotoxic effects on normal glial cells, highlighting their safety and selectivity. Moreover, the study highlights the immunomodulatory properties of UMSC/miR-124-PD-1 and its exosomes, enhancing the activation of immune cells such as T cells and dendritic cells, while reducing immunosuppressive cells populations like regulatory T cells and myeloid-derived suppressor cells. The orchestrated dual-gene delivery system by UMSCs and exosomes showcased targeted tumor inhibition and positive immune modulation, emphasizing its potential as a promising therapeutic approach for GBM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"107"},"PeriodicalIF":11.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711931","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":"AMP-activated protein kinase mediates adaptation of glioblastoma cells to conditions of the tumor microenvironment.","authors":"Nadja I Lorenz, Benedikt Sauer, Hans Urban, Jan-Béla Weinem, Bhavesh S Parmar, Pia S Zeiner, Maja I Strecker, Dorothea Schulte, Michel Mittelbronn, Tijna Alekseeva, Lisa Sevenich, Patrick N Harter, Christian Münch, Joachim P Steinbach, Anna-Luisa Luger, Dieter Henrik Heiland, Michael W Ronellenfitsch","doi":"10.1186/s13046-025-03346-2","DOIUrl":"10.1186/s13046-025-03346-2","url":null,"abstract":"<p><p>AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolic activity. We hypothesized that in glioblastoma (GB), AMPK plays a pivotal role in balancing metabolism under conditions of the tumor microenvironment with fluctuating and often low nutrient and oxygen availability. Impairment of this network could thus interfere with tumor progression. AMPK activity was modulated genetically by CRISPR/Cas9-based double knockout (DKO) of the catalytic α1 and α2 subunits in human GB cells and effects were confirmed by pharmacological AMPK inhibition using BAY3827 and an inactive control compound in primary GB cell cultures. We found that metabolic adaptation of GB cells under energy stress conditions (hypoxia, glucose deprivation) was dependent on AMPK and accordingly that AMPK DKO cells were more vulnerable to glucose deprivation or inhibition of glycolysis and sensitized to hypoxia-induced cell death. This effect was rescued by reexpression of the AMPK α2 subunit. Similar results were observed using the selective pharmacological AMPK inhibitor BAY3827. Mitochondrial biogenesis was regulated AMPK-dependently with a reduced mitochondrial mass and mitochondrial membrane potential in AMPK DKO GB cells. In vivo, AMPK DKO GB cells showed impaired tumor growth and tumor formation in CAM assays as well as in an orthotopic glioma mouse model. Our study highlights the importance of AMPK for GB cell adaptation towards energy depletion and emphasizes the role of AMPK for tumor formation in vivo. Moreover, we identified mitochondria as central downstream effectors of AMPK signaling. The development of AMPK inhibitors could open opportunities for the treatment of hypoxic tumors.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"104"},"PeriodicalIF":11.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694303","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":"Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism.","authors":"Ielizaveta Gorodetska, Vasyl Lukiyanchuk, Marta Gawin, Myroslava Sliusar, Annett Linge, Fabian Lohaus, Tobias Hölscher, Kati Erdmann, Susanne Fuessel, Angelika Borkowetz, Anna Wojakowska, Daniel Fochtman, Mark Reardon, Ananya Choudhury, Yasmin Antonelli, Aldo Leal-Egaña, Ayse Sedef Köseer, Uğur Kahya, Jakob Püschel, Andrea Petzold, Daria Klusa, Claudia Peitzsch, Romy Kronstein-Wiedemann, Torsten Tonn, Lukasz Marczak, Christian Thomas, Piotr Widłak, Monika Pietrowska, Mechthild Krause, Anna Dubrovska","doi":"10.1186/s13046-025-03299-6","DOIUrl":"10.1186/s13046-025-03299-6","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option available for metastatic PCa, and the clinical tests capable of predicting metastatic dissemination and metastatic response to the therapies are lacking. Our recent study identified aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa metastases. Still, the exact mechanisms mediating the role of these proteins in PCa metastatic dissemination remain not fully understood, and plasma-based biomarkers of these metastatic mechanisms are not available.</p><p><strong>Methods: </strong>Genetic silencing, gene overexpression, or treatment with different concentrations of the retinoic acid (RA) isomers, which are the products of ALDH catalytic activity, were used to modulate the interplay between retinoic acid receptors (RARs) and androgen receptor (AR). RNA sequencing (RNAseq), reporter gene assays, and chromatin immunoprecipitation (ChIP) analysis were employed to validate the role of RARs and AR in the regulation of the transforming growth factor-beta 1 (TGFB1) expression. Gene expression levels of ALDH1A1, ALDH1A3, and the matrix metalloproteinase 11 (MMP11) and their correlation with pathological parameters and clinical outcomes were analysed by mining several publicly available patient datasets as well as our multi-center transcriptomic dataset from patients with high-risk and locally advanced PCa. The level of MMP11 protein was analysed by enzyme-linked immunosorbent assay (ELISA) in independent cohorts of plasma samples from patients with primary or metastatic PCa and healthy donors, while plasma proteome profiles were obtained for selected subsets of PCa patients.</p><p><strong>Results: </strong>We could show that ALDH1A1 and ALDH1A3 genes differently regulate TGFB1 expression in a RAR- and AR-dependent manner. We further observed that the TGF-β1 pathway contributes to the regulation of the MMPs, including MMP11. We have confirmed the relevance of MMP11 as a promising clinical marker for PCa using several independent gene expression datasets. Further, we have validated plasma MMP11 level as a prognostic biomarker in patients with metastatic PCa. Finally, we proposed a hypothetical ALDH1A1/MMP11-related plasma proteome-based prognostic signature.</p><p><strong>Conclusions: </strong>TGFB1/MMP11 signaling contributes to the ALDH1A1-driven PCa metastases. MMP11 is a promising blood-based biomarker of PCa progression.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"105"},"PeriodicalIF":11.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694304","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":"Proteomic profiling and functional analysis of extracellular vesicles from metastasis-competent circulating tumor cells in colon cancer.","authors":"Luis Enrique Cortés-Hernández, Zahra Eslami-S, Aurore Attina, Silvia Batista, Laure Cayrefourcq, Jérôme Vialeret, Dolores Di Vizio, Christophe Hirtz, Bruno Costa-Silva, Catherine Alix-Panabières","doi":"10.1186/s13046-025-03360-4","DOIUrl":"10.1186/s13046-025-03360-4","url":null,"abstract":"<p><strong>Background: </strong>Circulating tumor cells (CTCs) are pivotal in cancer progression, and in vitro CTC models are crucial for understanding their biological mechanisms. This study focused on the characterization of extracellular vesicles (EVs) from CTC lines derived from a patient with metastatic colorectal cancer (mCRC) at different stages of progression who progressed despite therapy (thus mirroring the clonal evolution of cancer).</p><p><strong>Methods and results: </strong>Morphological and size analyses revealed variations among EVs derived from different CTC lines. Compared with the Vesiclepedia database, proteomic profiling of these EVs revealed enrichment of proteins related to stemness, endosomal biogenesis, and mCRC prognosis. Integrin family proteins were significantly enriched in EVs from CTC lines derived after therapy failure. The role of these EVs in cancer progression was analyzed by assessing their in vivo distribution, particularly in the liver, lungs, kidneys, and bones. EVs accumulate significantly in the liver, followed by the lungs, kidneys and femurs.</p><p><strong>Conclusions: </strong>This study is a pioneering effort in highlighting therapy progression-associated changes in EVs from mCRC patients via an in vitro CTC model. The results offer insights into the role of metastasis initiator CTC-derived EVs in cancer spread, suggesting their utility for studying cancer tissue distribution mechanisms. However, these findings must be confirmed and extended to patients with mCRC. This work underscores the potential of CTC-derived EVs as tools for understanding cancer dissemination.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"102"},"PeriodicalIF":11.4,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677402","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":"N⁴-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma.","authors":"Leyi Huang, Yanan Lu, Rihua He, Xiaofeng Guo, Jiajia Zhou, Zhiqiang Fu, Jingwen Li, Jianping Liu, Rufu Chen, Yu Zhou, Quanbo Zhou","doi":"10.1186/s13046-025-03362-2","DOIUrl":"10.1186/s13046-025-03362-2","url":null,"abstract":"<p><strong>Background: </strong>Perineural invasion (PNI) is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC), which occurs at a high incidence and significantly contributes to PDAC lethality and poor survival. Despite its prevalence and association with poor prognosis, the molecular mechanisms underlying PNI in PDAC remain unclear.</p><p><strong>Methods: </strong>We investigated clinical samples from two cohorts by UPLC/MS-MS to profiled significantly altered chemical RNA modifications in PDAC tissues with PNI lesions. Dorsal root ganglion coculture systems and sciatic nerve injection models validated PNI ability. We combined RNA-seq, acRIP-seq and ac4C-seq with CRISPR-based techniques to explore the regulatory mechanism of ac4C modification on the integrin beta 5 (ITGB5) transcript.</p><p><strong>Result: </strong>We reported that N⁴-acetylcytidine (ac4C) is a significantly altered chemical RNA modification in PDAC tissues with PNI lesions. In vitro and in vivo models demonstrated that tumor cells overexpression of N-acetyltransferase 10 (NAT10), the writer enzyme of mRNA ac4C modification, enhances PNI in PDAC. Further analysis revealed decreased ac4C levels on transcripts of the focal adhesion pathway, particular on ITGB5, in NAT10-knockdown PDAC cells. This ac4C modification in the CDS region of ITGB5 mRNA promotes its stability, subsequently activating the ITGB5-pFAK-pSrc pathway. CRISPR-based analysis further confirmed the crucial role of NAT10-mediated ac4C modification in regulating ITGB5 expression. Combining small-molecule inhibitors targeting NAT10 and focal adhesion kinase (FAK) significantly attenuated PNI in vivo.</p><p><strong>Conclusion: </strong>Our findings reveal a previously unrecognized ac4C-mediated epigenetic mechanism in PNI and propose a novel therapeutic strategy to improve survival in PDAC patients. NAT10 promotes PNI via ac4C modification in PDAC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"103"},"PeriodicalIF":11.4,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677401","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":"Retraction Note: Lnc-PDZD7 contributes to stemness properties and chemosensitivity in hepatocellular carcinoma through EZH2- mediated ATOH8 transcriptional repression.","authors":"Yi Zhang, Bo Tang, Jun Song, Shuiping Yu, Yang Li, Huizhao Su, Songqing He","doi":"10.1186/s13046-025-03364-0","DOIUrl":"10.1186/s13046-025-03364-0","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"101"},"PeriodicalIF":11.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671707","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":"CircPVT1 weakens miR-33a-5p unleashing the c-MYC/GLS1 metabolic axis in breast cancer.","authors":"Alina Catalina Palcau, Claudio Pulito, Valentina De Pascale, Luca Casadei, Mariacristina Valerio, Andrea Sacconi, Valeria Canu, Daniela Rutigliano, Sara Donzelli, Federica Lo Sardo, Francesca Romana Auciello, Fulvia Pimpinelli, Paola Muti, Claudio Botti, Sabrina Strano, Giovanni Blandino","doi":"10.1186/s13046-025-03355-1","DOIUrl":"10.1186/s13046-025-03355-1","url":null,"abstract":"<p><strong>Background: </strong>Altered metabolism is one of the cancer hallmarks. The role of circRNAs in cancer metabolism is poorly studied. Specifically, the impact of circPVT1, a well-known oncogenic circRNA on triple negative breast cancer metabolism is mechanistically underexplored.</p><p><strong>Methods: </strong>The clinical significance of circPVT1 expression levels was assessed in human breast cancer samples using digital PCR and the cancer genome atlas (TCGA) dataset. The oncogenic activity of circPVT1 was assessed in TNBC cell lines and in MCF-10 A breast cell line by either ectopic expression or depletion of circPVT1 molecule. CircPVT1 mediated metabolic perturbation was assessed by 1 H-NMR spectroscopy metabolic profiling. The binding of circPVT1 to miR-33a-5p and c-Myc recruitment onto the Glutaminase gene promoter were assessed by RNA immunoprecipitation and chromatin immunoprecipitation assays, respectively. The circPVT1/miR-33a-5p/Myc/GLS1 axis was functionally validated in breast cancer patients derived organoids. The viability of 2D and PDO cell models was assessed by ATP light assay and Opera Phenix plus high content screening.</p><p><strong>Results: </strong>We initially found that the expression of circPVT1 was significantly higher in tumoral tissues than in non-tumoral breast tissues. Basal like breast cancer patients with higher levels of circPVT1 exhibited shorter disease-free survival compared to those with lower expression. CircPVT1 ectopic expression rendered fully transformed MCF-10 A immortalized breast cells and increased tumorigenicity of TNBC cell lines. Depletion of endogenous circPVT1 reduced tumorigenicity of SUM-159PT and MDA-MB-468 cells. 1 H-NMR spectroscopy metabolic profiling of circPVT1 depleted breast cancer cell lines revealed reduced glycolysis and glutaminolitic fluxes. Conversely, MCF-10 A cells stably overexpressing circPVT1 exhibited increased glutaminolysis. Mechanistically, circPVT1 sponges miR-33a-5p, a well know metabolic microRNA, which in turn releases c-MYC activity promoting transcriptionally glutaminase. This activity facilitates the conversion of glutamine to glutamate. CircPVT1 depletion synergizes with GLS1 inhibitors BPTES or CB839 to reduce cell viability of breast cancer cell lines and breast cancer-derived organoids.</p><p><strong>Conclusions: </strong>In aggregate, our findings unveil the circPVT1/miR-33a-5p/Myc/GLS1 axis as a pro-tumorigenic metabolic event sustaining breast cancer transformation with potential therapeutic implications.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"100"},"PeriodicalIF":11.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671703","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":"PHGDH activation fuels glioblastoma progression and radioresistance via serine synthesis pathway.","authors":"Xiaojin Liu, Bangxin Liu, Junwen Wang, Hongbin Liu, Jiasheng Wu, Yiwei Qi, Yuan Liu, Hongtao Zhu, Chaoxi Li, Liu Yang, Jian Song, Guojie Yao, Weidong Tian, Kai Zhao, Lin Han, Kai Shu, Suojun Zhang, Jianghong Man, Chao You, Haohao Huang, Ran Li","doi":"10.1186/s13046-025-03361-3","DOIUrl":"10.1186/s13046-025-03361-3","url":null,"abstract":"<p><strong>Background: </strong>Glioma stem-like cells (GSCs) are key drivers of treatment resistance and recurrence in glioblastoma (GBM). Phosphoglycerate dehydrogenase (PHGDH), a crucial enzyme in the de novo serine synthesis pathway (SSP), is implicated in tumorigenesis and therapy resistance across various cancers. However, its specific role in GBM, particularly in radioresistance, remains poorly understood.</p><p><strong>Methods: </strong>In silico analysis of GBM patient data assessed SSP enrichment and PHGDH expression linked with tumor stemness. Comparative gene expression analysis focused on PHGDH in paired GBM specimens and GSCs. Genetic and pharmacological loss-of-function assays were performed in vitro and in vivo to evaluate PHGDH's impact on GSC self-renewal and malignant progression. Comprehensive transcriptomic and metabolomic analyses, along with chromatin immunoprecipitation, mass spectrometry, and various other biochemical assays, were used to elucidate PHGDH-mediated mechanisms in GBM progression and radioresistance.</p><p><strong>Results: </strong>PHGDH expression is significantly elevated in GSCs, associated with aggressive glioma progression and poor clinical outcomes. PHGDH activation enhances GSC self-renewal by regulating redox homeostasis, facilitating one-carbon metabolism, and promoting DNA damage response via SSP activation. Importantly, MYC was identified as a crucial transcriptional regulator of PHGDH expression. Furthermore, genetic ablation or pharmacological inhibition of PHGDH markedly reduced tumor growth and increased tumor sensitivity to radiotherapy, thereby improving survival outcomes in orthotopic GSC-derived and patient-derived GBM xenograft models.</p><p><strong>Conclusions: </strong>This study underscores the pivotal role of MYC-mediated PHGDH activation in driving GSC malignant progression and radioresistance in GBM. Targeting PHGDH presents a promising approach to enhance radiotherapy efficacy in GBM patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"99"},"PeriodicalIF":11.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659247","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}