Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Dysbiosis and extraintestinal cancers.","authors":"Ruishan He, Pingqian Qi, Linzhen Shu, Yidan Ding, Peng Zeng, Guosheng Wen, Ying Xiong, Huan Deng","doi":"10.1186/s13046-025-03313-x","DOIUrl":"10.1186/s13046-025-03313-x","url":null,"abstract":"<p><p>The gut microbiota plays a crucial role in safeguarding host health and driving the progression of intestinal diseases. Despite recent advances in the remarkable correlation between dysbiosis and extraintestinal cancers, the underlying mechanisms are yet to be fully elucidated. Pathogenic microbiota, along with their metabolites, can undermine the integrity of the gut barrier through inflammatory or metabolic pathways, leading to increased permeability and the translocation of pathogens. The dissemination of pathogens through the circulation may contribute to the establishment of an immune-suppressive environment that promotes carcinogenesis in extraintestinal organs either directly or indirectly. The oncogenic cascade always engages in the disruption of hormonal regulation and inflammatory responses, the induction of genomic instability and mutations, and the dysregulation of adult stem cell proliferation. This review aims to comprehensively summarize the existing evidence that points to the potential role of dysbiosis in the malignant transformation of extraintestinal organs such as the liver, breast, lung, and pancreas. Additionally, we delve into the limitations inherent in current methodologies, particularly the challenges associated with differentiating low loads gut-derived microbiome within tumors from potential sample contamination or symbiotic microorganisms. Although still controversial, an understanding of the contribution of translocated intestinal microbiota and their metabolites to the pathological continuum from chronic inflammation to tumors could offer a novel foundation for the development of targeted therapeutics.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"44"},"PeriodicalIF":11.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366696","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":"VSIG4⁺ tumor-associated macrophages mediate neutrophil infiltration and impair antigen-specific immunity in aggressive cancers through epigenetic regulation of SPP1.","authors":"Zongfu Pan, Jinming Chen, Tong Xu, Anqi Cai, Bing Han, Ying Li, Ziwen Fang, Dingyi Yu, Shanshan Wang, Junyu Zhou, Yingying Gong, Yulu Che, Xiaozhou Zou, Lei Cheng, Zhuo Tan, Minghua Ge, Ping Huang","doi":"10.1186/s13046-025-03303-z","DOIUrl":"10.1186/s13046-025-03303-z","url":null,"abstract":"<p><p>V-set and immunoglobulin domain-containing 4 (VSIG4) positive tumor-associated macrophage (VSIG4⁺ TAM) is an immunosuppressive subpopulation newly identified in aggressive cancers. However, the mechanism how VSIG4⁺ TAMs mediate immune evasion in aggressive cancers have not been fully elucidated. In our study, we found targeting VSIG4⁺ TAMs by VSIG4 deficiency or blockade remarkably limited tumor growth and metastasis, especially those derived from anaplastic thyroid cancer (ATC) and pancreatic cancer, two extremely aggressive types. Moreover, the combination of VSIG4 blockade with a BRAF inhibitor synergistically enhanced anti-tumor activity in ATC-tumor bearing mice. VSIG4 deficiency recovered the antigen presentation (B2m, H2-k1, H2-d1) of TAMs and activated antigen-specific CD8⁺ T cells by promoting their in vivo proliferation and intratumoral infiltration. Notably, loss of VSIG4 in TAMs significantly reduced the production of lactate and histone H3 lysine 18 lactylation, resulting the decreased transcription of SPP1 mediated by STAT3, which collectively disrupted the cell-cell interactions between TAMs and neutrophils. Further combination of VSIG4 with SPP1 blockade synergistically boosted anti-tumor activity. Overall, our studies demonstrate the epigenetic regulation function of VSIG4 confers on TAMs an alternative pattern, beyond the checkpoint role of VSIG4, to shape the immunosuppressive tumor microenvironment and impair antigen-specific immunity against aggressive cancers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"45"},"PeriodicalIF":11.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371437","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":"Preoperative liquid biopsy transcriptomic panel for risk assessment of lymph node metastasis in T1 gastric cancer.","authors":"Ping'an Ding, Jiaxiang Wu, Haotian Wu, Wenqian Ma, Tongkun Li, Peigang Yang, Honghai Guo, Yuan Tian, Jiaxuan Yang, Limian Er, Renjun Gu, Lilong Zhang, Ning Meng, Xiaolong Li, Zhenjiang Guo, Lingjiao Meng, Qun Zhao","doi":"10.1186/s13046-025-03305-x","DOIUrl":"10.1186/s13046-025-03305-x","url":null,"abstract":"<p><strong>Background: </strong>The increasing incidence of early-stage T1 gastric cancer (GC) underscores the need for accurate preoperative risk stratification of lymph node metastasis (LNM). Current pathological assessments often misclassify patients, leading to unnecessary radical surgeries.</p><p><strong>Methods: </strong>Through analysis of transcriptomic data from public databases and T1 GC tissues, we identified a 4-mRNA panel (SDS, TESMIN, NEB, and GRB14). We developed and validated a Risk Stratification Assessment (RSA) model combining this panel with clinical features using surgical specimens (training cohort: n = 218; validation cohort: n = 186), gastroscopic biopsies (n = 122), and liquid biopsies (training cohort: n = 147; validation cohort: n = 168).</p><p><strong>Results: </strong>The RSA model demonstrated excellent predictive accuracy for LNM in surgical specimens (training AUC = 0.890, validation AUC = 0.878), gastroscopic biopsies (AUC = 0.928), and liquid biopsies (training AUC = 0.873, validation AUC = 0.852). This model significantly reduced overtreatment rates from 83.9 to 44.1% in tissue specimens and from 84.4 to 56.0% in liquid biopsies. The 4-mRNA panel showed specificity for T1 GC compared to other gastrointestinal cancers (P < 0.001).</p><p><strong>Conclusions: </strong>We developed and validated a novel liquid biopsy-based RSA model that accurately predicts LNM in T1 GC patients. This non-invasive approach could significantly reduce unnecessary surgical interventions and optimize treatment strategies for high-risk T1 GC patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"43"},"PeriodicalIF":11.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366706","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":"Oncometabolite D-2HG drives tumor metastasis and protumoral macrophage polarization by targeting FTO/m⁶A/ANGPTL4/integrin axis in triple-negative breast cancer.","authors":"Siyue Zhang, Ning Zhang, Tong Wan, Yinqiao He, Jie Hao, Yiwei Liu, Yidong Liu, Bing Chen, Wenjing Zhao, Lijuan Wang, Dan Luo, Chao Gao, Qifeng Yang","doi":"10.1186/s13046-025-03282-1","DOIUrl":"10.1186/s13046-025-03282-1","url":null,"abstract":"<p><strong>Background: </strong>D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in breast cancer remains largely unexplored.</p><p><strong>Methods: </strong>We applied an advanced biosensor approach to detect the D-2HG levels in breast cancer samples. We then investigated the biological functions of D-2HG through multiple in vitro and in vivo assays. A joint MeRIP-seq and RNA-seq strategy was used to identify the target genes regulated by D-2HG-mediated N6-methyladenosine (m⁶A) modification. RNA pull-down assays were further applied to identify the reader that could specifically recognize the m⁶A modification on angiopoietin like 4 (ANGPTL4) mRNA and RNA immunoprecipitation was used to confirm the findings.</p><p><strong>Results: </strong>We found that D-2HG accumulated in triple-negative breast cancer (TNBC), exerting oncogenic effects both in vitro and in vivo by promoting TNBC cell growth and metastasis. Mechanistically, D-2HG enhanced global m⁶A RNA modifications in TNBC cells, notably upregulating m⁶A modification on ANGPTL4 mRNA, which was mediated by the inhibition of Fat-mass and obesity-associated protein (FTO), resulting in increased recognition of m⁶A-modified ANGPTL4 by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), thereby promoting the enhanced translation of ANGPTL4. As a secretory protein, ANGPTL4 subsequently activated the integrin-mediated JAK2/STAT3 signaling cascade in TNBC cells through autocrine signaling. Notably, the knockdown of ANGPTL4 or treatment with GLPG1087 (an integrin antagonist) significantly reduced D-2HG-induced proliferation and metastasis in TNBC cells. Additionally, ANGPTL4 was found to promote macrophage M2 polarization within the tumor microenvironment via paracrine signaling, further driving TNBC progression. The association of ANGPTL4 with poor prognosis in TNBC patients underscores its clinical relevance.</p><p><strong>Conclusions: </strong>Our study unveils a previously unrecognized role for D-2HG-mediated RNA modification in TNBC progression and targeting the D-2HG/FTO/m⁶A/ANGPTL4/integrin axis can serve as a promising therapeutic target for TNBC patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"41"},"PeriodicalIF":11.4,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257123","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":"TGF-β induces cholesterol accumulation to regulate the secretion of tumor-derived extracellular vesicles.","authors":"Dorival Mendes Rodrigues-Junior, Chrysoula Tsirigoti, Konstantina Psatha, Dimitris Kletsas, Michalis Aivaliotis, Carl-Henrik Heldin, Aristidis Moustakas","doi":"10.1186/s13046-025-03291-0","DOIUrl":"10.1186/s13046-025-03291-0","url":null,"abstract":"<p><strong>Background: </strong>Cancer cells are avid extracellular vesicle (EV) producers. EVs transport transforming growth factor-β (TGF-β), which is commonly activated under late stages of cancer progression. Nevertheless, whether TGF-β signaling coordinates EV biogenesis is a relevant topic that remains minimally explored.</p><p><strong>Method: </strong>We sought after specific TGF-β pathway mediators that could regulate EV release. To this end, we used a large number of cancer cell models, coupled to EV cell biological assays, unbiased proteomic and transcriptomic screens, followed by signaling and cancer biology analyses, including drug resistance assays.</p><p><strong>Results: </strong>We report that TGF-β, by activating its type I receptor and MEK-ERK1/2 signaling, increased the numbers of EVs released by human cancer cells. Upon examining cholesterol as a mediator of EV biogenesis, we delineated a pathway whereby ERK1/2 acted by phosphorylating sterol regulatory element-binding protein-2 that transcriptionally induced 7-dehydrocholesterol reductase expression, thus raising cholesterol abundance at both cellular and EV levels. Notably, inhibition of MEK or cholesterol synthesis, which impaired TGF-β-induced EV secretion, sensitized cancer cells to chemotherapeutic drugs. Furthermore, proteomic profiling of two distinct EV populations revealed that EVs secreted by TGF-β-stimulated cells were either depleted or enriched for different sets of cargo proteins. Among these, latent-TGF-β1 present in the EVs was not affected by TGF-β signaling, while TGF-β pathway-related molecules (e.g., matrix metalloproteinases, including MMP9) were either uniquely enriched on EVs or strongly enhanced after TGF-β stimulation. EV-associated latent-TGF-β1 activated SMAD signaling, even when EV uptake was blocked by heparin, indicating competent signaling capacity from target cell surface receptors. MMP inhibitor or proteinase treatment blocked EV-mediated SMAD signaling, suggesting that EVs require MMP activity to release the active TGF-β from its latent complex, a function also linked to the EV-mediated transfer of pro-migratory potential and ability of cancer cells to survive in the presence of cytotoxic drugs.</p><p><strong>Conclusion: </strong>Hence, we delineated a novel signaling cascade that leads to high rates of EV generation by cancer cells in response to TGF-β, with cholesterol being a key intermediate step in this mechanism.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"42"},"PeriodicalIF":11.4,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257125","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":"Developing a risk score using liquid biopsy biomarkers for selecting Immunotherapy responders and stratifying disease progression risk in metastatic melanoma patients.","authors":"Amalia Azzariti, Simona De Summa, Tommaso M Marvulli, Ivana De Risi, Giuseppe De Palma, Roberta Di Fonte, Rossella Fasano, Simona Serratì, Sabino Strippoli, Letizia Porcelli, Michele Guida","doi":"10.1186/s13046-025-03306-w","DOIUrl":"10.1186/s13046-025-03306-w","url":null,"abstract":"<p><strong>Background: </strong>Despite the high response rate to PD-1 blockade therapy in metastatic melanoma (MM) patients, a significant proportion of patients do not respond. Identifying biomarkers to predict patient response is crucial, ideally through non-invasive methods such as liquid biopsy.</p><p><strong>Methods: </strong>Soluble forms of PD1, PD-L1, LAG-3, CTLA-4, CD4, CD73, and CD74 were quantified using ELISA assay in plasma of a cohort of 110 MM patients, at baseline, to investigate possible correlations with clinical outcomes. A clinical risk prediction model was applied and validated in pilot studies.</p><p><strong>Results: </strong>No biomarker showed statistically significant differences between responders and non-responders. However, high number of significant correlations were observed among certain biomarkers in non-responders. Through univariate and multivariate Cox analyses, we identified sPD-L1, sCTLA-4, sCD73, and sCD74 as independent biomarkers predicting progression-free survival and overall survival. According to ROC analysis we discovered that, except for sCD73, values of sPD-L1, sCTLA-4, and sCD74 lower than the cut-off predicted lower disease progression and reduced mortality. A comprehensive risk score for predicting progression-free survival was developed by incorporating the values ​​of the two identified independent factors, sCTLA-4 and sCD74, which significantly improved the accuracy of outcome prediction. Pilot validations highlighted the potential use of the risk score in treatment-naive individuals and long responders.</p><p><strong>Conclusion: </strong>In summary, risk score based on circulating sCTLA-4 and sCD74 reflects the response to immune checkpoint inhibitor (ICI) therapy in MM patients. If confirmed, through further validation, these findings could assist in recommending therapy to patients likely to experience a long-lasting response.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"40"},"PeriodicalIF":11.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257121","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":"Targeting CXCL8 signaling sensitizes HNSCC to anlotinib by reducing tumor-associated macrophage-derived CLU.","authors":"Xin Hu, Yikang Ji, Mi Zhang, Zhihui Li, Xinhua Pan, Zhen Zhang, Xu Wang","doi":"10.1186/s13046-025-03298-7","DOIUrl":"10.1186/s13046-025-03298-7","url":null,"abstract":"<p><strong>Background: </strong>Although nutrition-starvation therapy for malignancies such as HNSCC is highly desirable, the clinical outcomes remain disappointing. Understanding the spatial heterogeneity of glucose deficiency can reveal the molecular mechanisms regulating cancer metabolism and identify therapeutic targets to improve effective nutrient-starvation therapies.</p><p><strong>Methods: </strong>Multiple omics data from RNA-seq, proteomics and spatial transcriptome analyses of HNSCC samples were integrated to analyze the spatial heterogeneity of glucose deficiency. In vivo and in vitro CXCL8 and CLU expression levels in tumor cells were determined using qPCR, immunohistochemistry and ELISA. The ability of CLU from TAMs to respond to tumor-derived CXCL8 was assessed using RNA sequencing, siRNA silencing, immunofluorescence and CCK-8 assays. A mouse subcutaneous xenograft model was used to assess the outcomes of nutrition-starvation therapy combined with blockade of CXCL8 signaling.</p><p><strong>Results: </strong>A set of genes that was significantly upregulated in HNSCC under conditions of glucose deficiency was identified using integrating multiple omics data analyses. The upregulated gene set was used to determine the glucose-deficient area according to transcriptome data of HNSCC, and CXCL8 was one of the most highly upregulated genes. The levels of both CXCL8 mRNA and its protein IL-8 in cancer cells under conditions of glucose deficiency were increased in an NF-κB-dependent manner. Supplementary IL-8 stimulated TAMs to synthesize CLU, and CLU counteracted oxidative stress in HNSCC cells under conditions of glucose deficiency. Moreover, pharmacological blockade of CXCL8 signaling (reparixin) sensitized HNSCC cells to nutrient-starvation therapy (anlotinib) in two xenograft models.</p><p><strong>Conclusion: </strong>Our results provide novel evidence of a feedback loop between cancer cells and TAMs in glucose-deficient regions. HNSCC-derived CXCL8 favors endogenous antioxidative processes and confers therapeutic resistance to nutrient-starvation therapies in HNSCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"39"},"PeriodicalIF":11.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190881","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":"EDF1 accelerates ganglioside GD3 accumulation to boost CD52-mediated CD8⁺ T cell dysfunction in neuroblastoma.","authors":"Di Li, Meng Li, Zhenjian Zhuo, Huiqin Guo, Weixin Zhang, Yile Xu, Hai-Yun Wang, Jiabin Liu, Huimin Xia, Huiran Lin, Jue Tang, Jing He, Lei Miao","doi":"10.1186/s13046-025-03307-9","DOIUrl":"10.1186/s13046-025-03307-9","url":null,"abstract":"<p><strong>Background: </strong>Heterogeneous clinical features and prognosis in neuroblastoma (NB) children are frequently dominated by immune elements. Dysfunction and apoptosis in immune cells result from the exposure to continuous tumor-related antigen stimulation and coinhibitory signals. To date, key factors pointing to the restriction of NB-specific CD8⁺ T cells remain elusive.</p><p><strong>Methods: </strong>We performed bulk-RNA sequencing and lipidomic analyses of children with mediastinal NB. Bioinformatics analysis and biological validation were applied to uncover the underlying mechanism.</p><p><strong>Results: </strong>Three subtypes were identified using nonnegative matrix factorization (NMF), among which we highlighted an apoptotic status of infiltrated CD8⁺ T cells, along with the highest CD52 and EDF1 expression in Cluster3 (C3) subtypes. It was verified that high EDF1 expression in NB cells led to Lactosylceramide (LacCer) accumulation, as well as downstream ganglioside-GD3, which subsequently increased the expression of CD52 and immune checkpoint genes, chemotaxis, and apoptosis-related events in activated CD8⁺T cells. Mechanistically, EDF1 was recruited as a coactivator to form the NF-κB/RelA/EDF1 complex, which further prevented the promoter region methylation of ST8SIA1, to elevate its transcription.</p><p><strong>Conclusion: </strong>These findings characterize abundant GD3 in NB cells, which regulated by the EDF1/RelA/ST8SIA1 axis, is responsible for CD8⁺ T cell dysfunction. Inhibition of EDF1 may reduce suppressive factors and prevent immune escape of NB cells. Modulating NB-associated GD3 levels through metabolic intervention is beneficial for tuning the depth and duration of responses to current NB therapies. The integration of transcriptomic and lipidomic data offers a more comprehensive understanding of the interaction between LacCer metabolites and the immune status in NB.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"36"},"PeriodicalIF":11.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190381","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":"EGFR inhibition augments the therapeutic efficacy of the NAT10 inhibitor Remodelin in Colorectal cancer.","authors":"Yongbin Zheng, Dan Song, Ming Guo, Chenhong Wang, Mingzhen Ma, Gongcai Tao, Licui Liu, Xiaobo He, Fengyu Cao, Dan Luo, Qingchuan Zhao, Zhongyuan Xia, Yanxin An","doi":"10.1186/s13046-025-03277-y","DOIUrl":"10.1186/s13046-025-03277-y","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and treatment options for advanced CRC are limited. The regulatory mechanisms of aberrant NAT10-mediated N4-acetylcytidine (ac4C) modifications in cancer progression remains poorly understood. Consequently, an integrated transcriptomic analysis is necessary to fully elucidate the role of NAT10-mediated ac4C modifications in CRC progression.</p><p><strong>Methods: </strong>NAT10 expression levels were analyzed in CRC samples and compared with those in corresponding normal tissues. The potential mechanisms of NAT10 in CRC were investigated using RNA sequencing, RNA immunoprecipitation sequencing, and acetylated RNA immunoprecipitation sequencing. Additional in vivo and in vitro experiments, including CCK-8 assays, colony formation and mouse xenograft models, were conducted to explore the biological role of NAT10-mediated ac4C modifications. We also evaluated and optimized a potential treatment strategy targeting NAT10.</p><p><strong>Results: </strong>We found that NAT10 is highly expressed in CRC samples and plays a pro-oncogenic role. NAT10 knockdown led to PI3K-AKT pathway inactivation, thereby inhibiting CRC progression. However, treatment with the NAT10 inhibitor Remodelin induced only a limited and reversible growth arrest in CRC cells. Further epigenetic and transcriptomic analysis revealed that NAT10 enhances the stability of ERRFI1 mRNA by binding to its coding sequence region in an ac4C-dependent manner. NAT10 knockdown decreased ERRFI1 expression, which subsequently activated the EGFR pathway and counteracted the inhibitory effects on CRC. Based on these findings, we demonstrated that dual inhibition of NAT10 and EGFR using Remodelin and the EGFR-specific monoclonal antibody cetuximab resulted in improved therapeutic efficacy compared to either drug alone. Moreover, we observed that 5-Fluorouracil promoted the interaction between NAT10 and UBR5, which increased the ubiquitin-mediated degradation of NAT10, leading to ERRFI1 downregulation and EGFR reactivation. Triple therapy with Remodelin, cetuximab, and 5-Fluorouracil enhanced tumor regression in xenograft mouse models of CRC with wild-type KRAS, NRAS and BRAF.</p><p><strong>Conclusions: </strong>Our study elucidated the mechanism underlying 5-Fu-induced NAT10 downregulation, revealing that NAT10 inhibition destabilizes ERRFI1 mRNA through ac4C modifications, subsequently resulting in EGFR reactivation. A triple therapy regimen of Remodelin, cetuximab, and 5-Fu showed potential as a treatment strategy for CRC with wild-type KRAS, NRAS and BRAF.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"37"},"PeriodicalIF":11.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190458","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: Combined treatment of glibenclamide and CoCl₂ decreases MMP9 expression and inhibits growth in highly metastatic breast cancer.","authors":"Zhe Rong, Li Li, Fei Fei, Lailong Luo, Yang Qu","doi":"10.1186/s13046-025-03311-z","DOIUrl":"10.1186/s13046-025-03311-z","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"38"},"PeriodicalIF":11.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190880","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}