Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Correction: 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/s13046-025-03384-w","DOIUrl":"https://doi.org/10.1186/s13046-025-03384-w","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"115"},"PeriodicalIF":11.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812810","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":"Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.","authors":"Su Jung Park, Claudia Cerella, Jin Mo Kang, Jinyoung Byun, David Kum, Barbora Orlikova-Boyer, Anne Lorant, Michael Schnekenburger, Ali Al-Mourabit, Christo Christov, Juyong Lee, Byung Woo Han, Marc Diederich","doi":"10.1186/s13046-025-03372-0","DOIUrl":"10.1186/s13046-025-03372-0","url":null,"abstract":"<p><strong>Background: </strong>Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis.</p><p><strong>Method: </strong>This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways.</p><p><strong>Results: </strong>TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells.</p><p><strong>Conclusion: </strong>TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"114"},"PeriodicalIF":11.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804649","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":"TRAF7 knockdown induces cellular senescence and synergizes with lomustine to inhibit glioma progression and recurrence.","authors":"Yu Chen, Tongyu Zhou, Rongrong Zhou, Wen Sun, Yan Li, Qiyi Zhou, Dongcheng Xu, Yuxin Zhao, Peihao Hu, Jingrui Liang, Yumeng Zhang, Bin Zhong, Juncheng Yao, Di Jing","doi":"10.1186/s13046-025-03363-1","DOIUrl":"10.1186/s13046-025-03363-1","url":null,"abstract":"<p><strong>Background: </strong>The progression and recurrence are the fatal prognostic factors in glioma patients. However, the therapeutic role and potential mechanism of TRAF7 in glioma patients remain largely unknown.</p><p><strong>Methods: </strong>TRAF7 RNA-seq was analysed with the TCGA and CGGA databases between glioma tissues and normal brain tissues. The expression of TRAF7, cellular senescence and cell cycle arrest pathways in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The interaction between TRAF7 and KLF4 was determined by Co-immunoprecipitation (Co-IP) assays. The functions of TRAF7 combined with lomustine in glioma were assessed by both in vitro, in vivo and patient-derived primary and recurrent glioma stem cell (GSC) assays.</p><p><strong>Results: </strong>High TRAF7 expression is closely associated with a higher recurrence rate and poorer overall survival (OS). In vitro, TRAF7 knockdown significantly inhibits glioma cell proliferation, invasion, and migration. RNA-seq analysis revealed that TRAF7 inhibition activates pathways related to cellular senescence and cell cycle arrest. In both in vitro and patient-derived GSC assays, the combination of sh-TRAF7 and lomustine enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest, surpassing the effects of lomustine or TRAF7 inhibition alone. Mechanistically, TRAF7 interacts with KLF4, and a rescue assay demonstrated that KLF4 overexpression could reverse the effects of TRAF7 depletion on proliferation and cellular senescence. In vivo, TRAF7 knockdown combined with lomustine treatment effectively suppressed glioma growth.</p><p><strong>Conclusion: </strong>TRAF7 could be used as a predictive biomarker and the potential therapeutic target among National Comprehensive Cancer Network (NCCN) treatment guidelines in the progression and recurrence of glioma. Lomustine, regulating cellular senescence and cell cycle could be the priority choice in glioma patients with high-level TRAF7 expression.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"112"},"PeriodicalIF":11.4,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781749","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":"CCR8 antagonist suppresses liver cancer progression via turning tumor-infiltrating Tregs into less immunosuppressive phenotype.","authors":"Binle Tian, Zhilong Wang, Mei Cao, Na Wang, Xuebing Jia, Yuanyuan Zhang, Jingyi Zhou, Sijia Liu, Wen Zhang, Xiao Dong, Zheng Li, Junli Xue, JianFei Wang, Guo-Huang Fan, Qi Li","doi":"10.1186/s13046-025-03286-x","DOIUrl":"10.1186/s13046-025-03286-x","url":null,"abstract":"<p><strong>Background: </strong>Regulatory T cells (Tregs) are the main immunosuppressive cells in tumor immune microenvironment (TIME). However, systemic Treg depletion is not favored due to the crucial role of Tregs in the maintenance of immune homeostasis and prevention of autoimmunity. Recently, CCR8 has been identified as a key chemokine receptor expressed on tumor-infiltrating Tregs and targeted blockade of CCR8 exerts anticancer effect in several cancer types, but whether this pathway is involved in the progression of hepatocellular carcinoma (HCC) remains unclear.</p><p><strong>Methods: </strong>We determined the involvement of CCR8⁺ Tregs in HCC using human HCC tissues and TCGA database, and examined the anticancer effect and the underlying molecular mechanisms of the CCR8 antagonist, IPG0521m, which was developed in house, in murine liver cancer model with flow cytometry, bulk and single-cell RNA sequencing and Real-Time PCR.</p><p><strong>Results: </strong>Remarkable increase in CCR8⁺ Tregs was observed in human HCC tissues. Treatment of syngeneic liver cancer model with IPG0521m resulted in dramatic inhibition of tumor growth, associated with increased CD8⁺ T cells in tumor tissues. Bulk RNA sequencing analysis indicated that IPG0521m treatment resulted in remarkable increase in antitumor immunity. Furthermore, single-cell RNA sequencing analysis demonstrated that IPG0521m treatment resulted in a switch of Tregs from high immunosuppression to low immunosuppression phenotype, associated with elevated CD8⁺ T and NK cell proliferation and cytotoxicity, and decreased myeloid-derived suppressor cells and tumor-associated macrophages in the tumor tissues.</p><p><strong>Conclusions: </strong>IPG0521m inhibited liver cancer growth via reducing the immunosuppressive function of Tregs, thereby boosting anti-cancer immunity. Our study paves the way for the clinical study of CCR8 antagonist in HCC and other cancers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"113"},"PeriodicalIF":11.4,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789143","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":"Transcriptional profiles of circulating tumor cells reflect heterogeneity and treatment resistance in advanced prostate cancer.","authors":"Lina Bergmann, Sarah Greimeier, Sabine Riethdorf, Tina Rohlfing, Moritz Kaune, Tobias Busenbender, Nadja Strewinsky, Sergey Dyshlovoy, Simon Joosse, Sven Peine, Klaus Pantel, Gunhild von Amsberg, Stefan Werner","doi":"10.1186/s13046-025-03367-x","DOIUrl":"10.1186/s13046-025-03367-x","url":null,"abstract":"<p><strong>Purpose: </strong>New biomarkers for the detection and monitoring of aggressive variant prostate cancer (AVPC) including therapy-induced neuroendocrine prostate cancer (NEPC) are urgently needed, as measuring prostate-specific antigen (PSA) is not reliable in androgen-indifferent diseases. Molecular analysis of circulating tumor cells (CTC) enables repeated analysis for monitoring and allows to capture the heterogeneity of the disease.</p><p><strong>Experimental design: </strong>102 blood samples from 76 metastatic prostate cancer (mPC) patients, including 37 samples from histologically proven NEPC, were collected and CTCs were enriched using label-dependent and label-independent methods. Relevant transcripts were selected for CTC profiling using semi-quantitative RT-PCR analysis and validated in published datasets and cell lines. Transcriptional profiles in patient samples were analyzed using supervised and unsupervised methods.</p><p><strong>Results: </strong>CTC counts were increased in AVPC and NEPC as compared to metastatic hormone-sensitive prostate cancer (mHSPC). Gene expression profiles of CTCs showed a high degree of inter-patient heterogeneity, but NEPC-specific transcripts were significantly increased in patients with proven NEPC, while adenocarcinoma markers were decreased. Unsupervised analysis identified four distinct clusters of CTC^low, AR^high, amphicrine and pure NEPC gene expression profiles that reflected the clinical groups. Based on the transcript panel, NEPC could be distinguished from mHSPC or AVPC patients with a specificity of 95.5% and 88.2%, respectively.</p><p><strong>Conclusion: </strong>Molecular subtypes of mPC can be distinguished by transcriptional profiling of CTCs. In the future, our convenient PCR-based analysis may complement the monitoring of advanced PCa patients and allow timely detection of resistance to androgen receptor pathway inhibitors.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"111"},"PeriodicalIF":11.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781750","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":"o8G-modified circKIAA1797 promotes lung cancer development by inhibiting cuproptosis.","authors":"Haotian Xu, Qingyun Zhao, Dunyu Cai, Xingcai Chen, Xiaodong Zhou, Yihong Gao, Jiaxi Wu, Shengyi Yuan, Deqing Li, Ruirui Zhang, Wenyi Peng, Gang Li, Aruo Nan","doi":"10.1186/s13046-025-03365-z","DOIUrl":"10.1186/s13046-025-03365-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Lung cancer is a serious threat to human life and health, but effective screening and treatment methods are lacking. Circular RNAs (circRNAs) have important biological functions and are closely related to tumour development. Some studies have shown that the 8-oxo-7,8-dihydroguanosine (o8G) modification plays a key role in the disease process, but the effect of the o8G modification on circRNAs has not been elucidated. Moreover, cuproptosis is a novel mode of cell death in which copper ions directly promote protein aggregation and the disruption of cellular metabolic pathways. The present study revealed that the o8G modification of circKIAA1797 occurs and promotes lung cancer development by inhibiting cuproptosis, which provides new perspectives for epitranscriptomic studies and the development of novel therapeutic approaches for lung cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;circRNA differential expression profiles in lung cancer were revealed via RNA high-throughput sequencing, and circKIAA1797 expression in lung cancer cell lines and tissues was detected using qPCR. Experiments such as o8G RNA immunoprecipitation (o8G RIP) and crosslinking immunoprecipitation (CLIP) were performed to explore the presence of o8G on circKIAA1797. The regulation of circKIAA1797 by the o8G reader Y-box binding protein 1 (YBX1) was explored using nuclear-cytoplasmic fractionation, actinomycin D (Act D) stability experiments and other experiments. circKIAA1797 silencing and overexpression systems were constructed for in vivo and in vitro experiments to study the role of circKIAA1797 in lung cancer development. Tagged RNA affinity purification (TRAP), RNA immunoprecipitation (RIP), coimmunoprecipitation (Co-IP), and immunofluorescence (IF) staining were subsequently conducted to reveal the molecular mechanism by which circKIAA1797 regulates cuproptosis and promotes lung cancer development.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;This study is the first to reveal the presence of o8G on circKIAA1797 and that YBX1 is a reader that recognises ROS-induced circKIAA1797 o8G modifications and increases the stability and cytoplasmic expression of circKIAA1797. circKIAA1797, which is associated with the tumour stage and prognosis, has been shown to significantly promote the biological function of lung cancer development both in vivo and in vitro. This study revealed that circKIAA1797 inhibits intracellular cuproptosis by binding to the ferredoxin 1 (FDX1) mRNA, decreasing FDX1 mRNA stability, inhibiting FDX1 expression, and binding to the signal transducer and activator of transcription 1 (STAT1) protein and inhibiting lipoyltransferase 1 (LIPT1) transcription; moreover, circKIAA1797 promotes the closure of the mitochondrial permeability transition pore (mPTP), inhibits cuproptosis, and ultimately promotes lung cancer development.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study revealed the presence of the o8G modification in circKIAA1797, which plays an imp","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"110"},"PeriodicalIF":11.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774647","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":"Role of inflammasomes in cancer immunity: mechanisms and therapeutic potential.","authors":"Vivek Singh, Saba Ubaid, Mohammad Kashif, Tanvi Singh, Gaurav Singh, Roma Pahwa, Anand Singh","doi":"10.1186/s13046-025-03366-y","DOIUrl":"https://doi.org/10.1186/s13046-025-03366-y","url":null,"abstract":"<p><p>Inflammasomes are multi-protein complexes that detect pathogenic and damage-associated molecular patterns, activating caspase-1, pyroptosis, and the maturation of pro-inflammatory cytokines such as IL-1β and IL-18Within the tumor microenvironment, inflammasomes like NLRP3 play critical roles in cancer initiation, promotion, and progression. Their activation influences the crosstalk between innate and adaptive immunity by modulating immune cell recruitment, cytokine secretion, and T-cell differentiation. While inflammasomes can contribute to tumor growth and metastasis through chronic inflammation, their components also present novel therapeutic targets. Several inhibitors targeting inflammasome components- such as sensor proteins (e.g., NLRP3, AIM2), adaptor proteins (e.g., ASC), caspase-1, and downstream cytokines- are being explored to modulate inflammasome activity. These therapeutic strategies aim to modulate inflammasome activity to enhance anti-tumor immune responses and improve clinical outcomes. Understanding the role of inflammasomes in cancer immunity is crucial for developing interventions that effectively bridge innate and adaptive immune responses for better therapeutic outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"109"},"PeriodicalIF":11.4,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744195","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":"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}