Journal of Experimental & Clinical Cancer Research最新文献

{"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}

{"title":"Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy.","authors":"Yonghua Cai, Heng Xiao, Shuaishuai Xue, Peng Li, Zhengming Zhan, Jie Lin, Zibin Song, Jun Liu, Wei Xu, Qixiong Zhou, Songtao Qi, Xi'an Zhang, Ziyi Luo","doi":"10.1186/s13046-025-03301-1","DOIUrl":"10.1186/s13046-025-03301-1","url":null,"abstract":"<p><strong>Background: </strong>Glioma, particularly glioblastoma (GBM), is a highly aggressive tumor with limited responsiveness to immunotherapy. PANoptosis, a form of programmed cell death merging pyroptosis, apoptosis, and necroptosis, plays an important role in reshaping the tumor microenvironment (TME) and enhancing immunotherapy effectiveness. This study investigates PANoptosis dynamics in glioma and explores the therapeutic potential of its activation, particularly through natural compounds such as cinobufagin.</p><p><strong>Methods: </strong>We comprehensively analyzed PANoptosis-related genes (PANoRGs) in multiple glioma cohorts, identifying different PANoptosis patterns and constructing the PANoptosis enrichment score (PANoScore) to evaluate its relationship with patient prognosis and immune activity. Cinobufagin, identified as a PANoptosis activator, was evaluated for its ability to induce PANoptosis and enhance anti-tumor immune responses both in vitro and in vivo GBM models.</p><p><strong>Results: </strong>Our findings indicate that high PANoScore gliomas showed increased immune cell infiltration, particularly effector T cells, and enhanced sensitivity to immunotherapies. Cinobufagin effectively induced PANoptosis, leading to increased immunogenic cell death, facilitated tumor-associated microglia/macrophages (TAMs) polarization towards an M1-like phenotype while augmenting CD4+/CD8 + T cell infiltration and activation. Importantly, cinobufagin combined with anti-PD-1 therapy exhibited significant synergistic effects and prolonged survival in GBM models.</p><p><strong>Conclusions: </strong>These findings highlight the therapeutic potential of PANoptosis-targeting agents, such as cinobufagin, in combination with immunotherapy, offering a promising approach to convert \"cold\" tumors into \"hot\" ones and improving glioma treatment outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"35"},"PeriodicalIF":11.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11789371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143124062","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":"Correction: Stearoyl-CoA desaturase-1 promotes colorectal cancer metastasis in response to glucose by suppressing PTEN.","authors":"Hui Ran, Yemin Zhu, Ruyuan Deng, Qi Zhang, Xisheng Liu, Ming Feng, Jie Zhong, Shuhai Lin, Xuemei Tong, Qing Su","doi":"10.1186/s13046-025-03300-2","DOIUrl":"10.1186/s13046-025-03300-2","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"34"},"PeriodicalIF":11.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076268","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":"Myeloid cell-derived apCAFs promote HNSCC progression by regulating proportion of CD4⁺ and CD8⁺ T cells.","authors":"Feilong Ren, Lin Meng, Shize Zheng, Jiasen Cui, Shaoyi Song, Xing Li, Dandan Wang, Xing Li, Qilin Liu, Wenhuan Bu, Hongchen Sun","doi":"10.1186/s13046-025-03290-1","DOIUrl":"10.1186/s13046-025-03290-1","url":null,"abstract":"<p><p>It is well-known that cancer-associated fibroblasts (CAFs) are involved in the desmoplastic responses in Head and Neck Squamous Cell Carcinoma (HNSCC). CAFs are pivotal in the tumor microenvironment (TME) molding, and exert a profound influence on tumor development. The origin and roles of CAFs, however, are still unclear in the HNSCC, especially antigen-presenting cancer-associated fibroblasts (apCAFs). Our current study tried to explore the origin, mechanism, and function of the apCAFs in the HNSCC. Data from single-cell transcriptomics elucidated the presence of apCAFs in the HNSCC. Leveraging cell trajectory and Cellchat analysis along with robust lineage-tracing assays revealed that apCAFs were primarily derived from myeloid cells. This transdifferentiation was propelled by the macrophage migration inhibitory factor (MIF), which was secreted by tumor cells and activated the JAK/STAT3 signaling pathway. Analysis of the TCGA database has revealed that markers of apCAFs were inversely correlated with survival rates in patients with HNSCC. In vivo experiments have demonstrated that apCAFs could facilitate tumor progression. Furthermore, apCAFs could modulate ratio of CD4⁺ T cells/CD8⁺ T cells, such as higher ratio of CD4⁺ T cells/CD8⁺ T cells could promote tumor progression. Most importantly, data from in vivo assays revealed that inhibitors of MIF and p-STAT3 could significantly inhibit the OSCC growth. Therefore, our findings show potential innovative therapeutic approaches for the HNSCC.Significance: ApCAFs derived from myeloid cells promote the progression of HNSCC by increasing the ratio of CD4⁺/CD8⁺ cells, indicating potential novel targets to be used to treat the human HNSCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"33"},"PeriodicalIF":11.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076271","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":"Enhancing immunotherapy efficacy with synergistic low-dose radiation in metastatic melanoma: current insights and prospects.","authors":"Zahid Rafiq, Mingyo Kang, Hampartsoum B Barsoumian, Gohar S Manzar, Yun Hu, Carola Leuschner, Ailing Huang, Fatemeh Masrorpour, Weiqin Lu, Nahum Puebla-Osorio, James W Welsh","doi":"10.1186/s13046-025-03281-2","DOIUrl":"10.1186/s13046-025-03281-2","url":null,"abstract":"<p><p>Recent advances in oncology research have highlighted the promising synergy between low-dose radiation therapy (LDRT) and immunotherapies, with growing evidence highlighting the unique benefits of the combination. LDRT has emerged as a potent tool for stimulating the immune system, triggering systemic antitumor effects by remodeling the tumor microenvironment. Notably, LDRT demonstrates remarkable efficacy even in challenging metastatic sites such as the liver (uveal) and brain (cutaneous), particularly in advanced melanoma stages. The increasing interest in utilizing LDRT for secondary metastatic sites of uveal, mucosal, or cutaneous melanomas underscores its potential efficacy in combination with various immunotherapies. This comprehensive review traverses the journey from laboratory research to clinical applications, elucidating LDRT's immunomodulatory role on the tumor immune microenvironment (TIME) and systemic immune responses. We meticulously examine the preclinical evidence and ongoing clinical trials, throwing light on the promising prospects of LDRT as a complementary therapy in melanoma treatment. Furthermore, we explore the challenges associated with LDRT's integration into combination therapies, addressing crucial factors such as optimal dosage, fractionation, treatment frequency, and synergy with other pharmacological agents. Considering its low toxicity profile, LDRT presents a compelling case for application across multiple lesions, augmenting the antitumor immune response in poly-metastatic disease scenarios. The convergence of LDRT with other disciplines holds immense potential for developing novel radiotherapy-combined modalities, paving the way for more effective and personalized treatment strategies in melanoma and beyond. Moreover, the dose-related toxicities of immunotherapies may be reduced by synergistic amplification of antitumor efficacy with LDRT.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"31"},"PeriodicalIF":11.4,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069313","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":"Extracellular matrix stiffness regulates colorectal cancer progression via HSF4.","authors":"Kangtao Wang, Siyi Ning, Shuai Zhang, Mingming Jiang, Yan Huang, Haiping Pei, Ming Li, Fengbo Tan","doi":"10.1186/s13046-025-03297-8","DOIUrl":"10.1186/s13046-025-03297-8","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) has high incidence and mortality rates, with severe prognoses during invasion and metastasis stages. Despite advancements in diagnostic and therapeutic technologies, the impact of the tumour microenvironment, particularly extracellular matrix (ECM) stiffness, on CRC progression and metastasis is not fully understood.</p><p><strong>Methods: </strong>This study included 107 CRC patients. Tumour stiffness was assessed using magnetic resonance elastography (MRE), and collagen ratio was analysed with Masson staining. CRC cell lines were cultured on matrices of varying stiffness, followed by transcriptome sequencing to identify stiffness-related genes. An HSF4 knockout CRC cell model was cultured in different ECM stiffness to evaluate the effects of HSF4 on cell proliferation, migration, and invasion in vitro and in vivo.</p><p><strong>Results: </strong>CRC tumour stiffness was significantly higher than normal tissue and positively correlated with collagen content and TNM staging. High-stiffness matrices significantly regulated cell functions and signalling pathways. High HSF4 (heat shock transcriptional factor 4) expression was strongly associated with tumour stiffness and poor prognosis. HSF4 expression increased with higher TNM stages, and its knockout significantly inhibited cell proliferation, migration, and invasion, especially on high-stiffness matrices. In vivo experiments confirmed that HSF4 promoted tumour growth and metastasis, independent of collagen protein increase.</p><p><strong>Conclusions: </strong>This study reveals that tumour stiffness promotes the proliferation and metastasis of CRC by regulating EMT-related signalling pathways through HSF4. Tumour stiffness and HSF4 could be valuable targets for prognostic assessment and therapeutic intervention in CRC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"30"},"PeriodicalIF":11.4,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069316","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}