{"title":"Integrated metabolomic and transcriptomic analysis identifies adipogenic differentiation of mesenchymal stem cells as a driver of chemoresistance in acute myeloid leukemia.","authors":"Zhipeng Pan, Rong Hu, Dandan Li, Siwen Deng, Haishan Yi, Zhengwei Duan, Lixia Kang, Ling Chen, Mengyao Wang, Yue Duan, Xiaofan Jia, Pengfei Guo, Yang Chen","doi":"10.1186/s13046-025-03550-0","DOIUrl":"10.1186/s13046-025-03550-0","url":null,"abstract":"<p><strong>Background: </strong>Acute myeloid leukemia (AML) remains a challenging hematological malignancy, with chemoresistance contributing significantly to treatment failure and relapse. The bone marrow microenvironment, particularly mesenchymal stem cells (MSCs), plays a critical role in AML cell survival and drug resistance. Although previous studies have extensively explored the MSCs differentiation, the regulatory role of the adipogenically differentiated MSCs on AML cells during co-culture remains unclear.</p><p><strong>Methods: </strong>An indirect co-culture model was established to evaluate the impact of MSCs on the drug sensitivity of AML cells. Based on the comparable chemosensitivity trends observed among THP-1, U937, and HL-60 cells, THP-1 were selected for subsequent experiments due to their stable growth characteristics and well-established utilization. Metabolic alterations between co-cultured and monocultured THP-1 were profiled using nuclear magnetic resonance spectroscopy. Concurrently, RNA sequencing was conducted to identify differentially expressed genes and enriched signaling pathways between co-cultured and monocultured THP-1. To validate the pathway alterations identified by transcriptomic analysis, the Akt inhibitor MK-2206 was applied, and its effects were evaluated by western blotting and cell viability assays.</p><p><strong>Results: </strong>The results demonstrated that AML cells co-cultured with adipogenic MSCs were less sensitive to daunorubicin and cytarabine in both in vitro and in vivo. Subsequent metabolomics analysis revealed significant alternative metabolic processes in AML cells following co-culture, specifically in the glycolysis, glutamine metabolism and lipid metabolism. Further transcriptomic profiling identified key differentially expressed genes and signaling pathways, with PI3K/Akt signaling pathway activation emerging as a contributor to the reduced chemotherapy sensitivity. Furthermore, elevated levels of IL-6 in the co-culture system suggested a role for cytokine-mediated signaling in promoting a protective microenvironment.</p><p><strong>Conclusions: </strong>This work demonstrates that the adipogenically differentiated MSCs enhance the survival and chemoresistance of AML cells by modulating metabolic and signaling pathways. It provides integrated insights into the microenvironment-driven mechanisms of AML drug resistance and presents potential therapeutic targets to enhance treatment efficacy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"291"},"PeriodicalIF":12.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12534991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314117","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}
Mohammed Moustapha Anwar, Salvador Meseguer, Néstor García-Rodríguez, Ewa Krupinska, Céleste Sele, Aida Rodríguez-Jiménez, Suraj Verma, Samna Sagadevan, Javier Ramon, Ramon Martí, Annalisa Occhipinti, Claudio Angione, Paloma Ordóñez-Morán, Wolfgang Knecht, Pablo Huertas, M Angeles Juanes
{"title":"NK-A 17E-233I: a novel competitive inhibitor of human dihydroorotate dehydrogenase (DHODH) for cancer therapy.","authors":"Mohammed Moustapha Anwar, Salvador Meseguer, Néstor García-Rodríguez, Ewa Krupinska, Céleste Sele, Aida Rodríguez-Jiménez, Suraj Verma, Samna Sagadevan, Javier Ramon, Ramon Martí, Annalisa Occhipinti, Claudio Angione, Paloma Ordóñez-Morán, Wolfgang Knecht, Pablo Huertas, M Angeles Juanes","doi":"10.1186/s13046-025-03538-w","DOIUrl":"10.1186/s13046-025-03538-w","url":null,"abstract":"<p><p>Human dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in pyrimidine de novo synthesis and represents a promising target for cancer therapy. However, current inhibitors of DHODH have limited clinical effectiveness and adverse effects. Herein, we report NK-A 17E-233I, a novel small-molecule inhibitor of the human DHODH enzyme, identified through a prospective virtual screening methodology. Molecular docking and biochemical assays show NK-A 17E-233I functions as a pure or partial competitive inhibitor with respect to the natural substrate, dihydroorotate (DHO). It adopts a distinct binding mode from classical inhibitors that target the flavin mononucleotide (FMN) binding cavity of the hydrophobic tunnel. NK-A 17E-233I exhibits selective cytotoxicity in both human cancer cell lines and patient-derived intestinal organoids, inducing DNA damage, S-phase arrest, and cell death. Unlike Brequinar, NK-A 17E-233I preserves mitochondrial respiration via complexes I and II and maintains ATP-linked basal respiration, avoiding the impairment of the electron transport chain (ETC). Our findings imply the aptitude of NK-A 17E-233I as a novel competitive inhibitor of human DHODH, representing a significant advancement in this field since the 1990s.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"292"},"PeriodicalIF":12.8,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12534982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314164","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}
Juening Kang, Panagiotis Chouvardas, Andrew Maalouf, Daniel Hanhart, Laura Fernández Cerro, Wanli Cheng, Eva Compérat, Katja Ovchinnikova, Rahel Etter, Michaela Medová, Ulrich Schneeberger, Beat Roth, George N Thalmann, Sofia Karkampouna, Marianna Kruithof-de Julio
{"title":"Multi-layer stratified oncology platform utilizing transcriptomics, prostate cancer organoids, and modeling of drug response.","authors":"Juening Kang, Panagiotis Chouvardas, Andrew Maalouf, Daniel Hanhart, Laura Fernández Cerro, Wanli Cheng, Eva Compérat, Katja Ovchinnikova, Rahel Etter, Michaela Medová, Ulrich Schneeberger, Beat Roth, George N Thalmann, Sofia Karkampouna, Marianna Kruithof-de Julio","doi":"10.1186/s13046-025-03540-2","DOIUrl":"10.1186/s13046-025-03540-2","url":null,"abstract":"<p><p>The high intra-patient heterogeneity in multifocal primary prostate cancer (PCa) has curtailed the efficacy of current treatment options. By employing twin biopsies from multiple lesions with matched patient-derived organoids (PDO) models, the PCa molecular heterogeneity was investigated. We utilized genomics, transcriptomics and machine learning (ML) approaches to elucidate and predict the underlying mechanisms of pharmacological heterogeneity. Our data indicate a vulnerability of primary PCa organoids for small molecule inhibitors targeting receptor tyrosine kinases (MET, ALK, SRC). By exploring gene expression data from matched parental tissue in an unsupervised manner, we identified two distinct clusters of samples. Interestingly, the PDO drug responses were significantly different between the two clusters for 4/11 compounds tested. We developed a transcriptomics-based, cluster prediction model, which can accurately stratify samples into the two clusters. Notably, our prediction model is based on tissue profiles, therefore, it can be utilized to rapidly evaluate new cases and suggest promising drug candidates, even when PDO derivation is not feasible. Taken together, we propose a novel flexible stratified oncology approach that can swiftly and accurately highlight promising drug vulnerabilities of PCa patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"290"},"PeriodicalIF":12.8,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12529805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304202","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":"FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination.","authors":"Zhiwen Qian, Ying Jiang, Yun Cai, Erli Gao, Cenzhu Wang, Jianfeng Dong, Fengxu Wang, Lu Liu, Danping Wu, Feng Zhang, Yida Wang, Xin Ning, Qi Li, Yilan You, Yanfang Gu, Jie Mei, Xinyuan Zhao, Yan Zhang","doi":"10.1186/s13046-025-03548-8","DOIUrl":"10.1186/s13046-025-03548-8","url":null,"abstract":"<p><p>Increasing studies have reported that dysregulated lipid metabolism is an independent risk factor for breast cancer (BC); it would be, therefore, enlightening to investigate the relationship between metabolic reprogramming and the tumor microenvironment in the future. Ferroptosis, a novel form of programmed cell death, is characterized by glutathione (GSH) depletion and inactivation of glutathione peroxidase 4 (GPX4), the central regulator of the antioxidant system. While the close association between fatty acid metabolism and ferroptosis has been studied in various diseases, the interplay between the key fatty acid metabolic enzyme fatty acid synthase (FASN) and ferroptosis in BC remains unexplored. At the beginning of the current study, we demonstrated that FASN expression positively correlates with an immune-cold tumor microenvironment in BC. Subsequent findings revealed that FASN knockdown promotes GPX4 degradation-induced ferroptosis, thereby enhancing the efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy. Co-immunoprecipitation coupled with mass spectrometry (IP/MS) and co-IP experiments demonstrated that ubiquitin specific protease 5 (USP5) stabilizes GPX4 by binding to and deubiquitinating it. Furthermore, knockdown of FASN inhibited the palmitoylation of USP5, reducing its interaction with GPX4 and consequently increasing GPX4 ubiquitination and degradation. Our results demonstrate that FASN suppresses ferroptosis in BC by stabilizing GPX4 via USP5-mediated mechanisms, highlighting FASN inhibition as a potential therapeutic approach to enhance immunotherapy response.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"289"},"PeriodicalIF":12.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12523187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294231","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}
Marcel Mayer, Lisa Nachtsheim, Louis Jansen, Philipp Wolber, Marcel Schmiel, Luc G T Morris, Fengshen Kuo, Alan L Ho, Alexander Quaas, Jens Peter Klussmann, Christoph Arolt
{"title":"Deciphering the cellular tumor microenvironment landscape in salivary gland carcinomas using multiplexed imaging mass cytometry.","authors":"Marcel Mayer, Lisa Nachtsheim, Louis Jansen, Philipp Wolber, Marcel Schmiel, Luc G T Morris, Fengshen Kuo, Alan L Ho, Alexander Quaas, Jens Peter Klussmann, Christoph Arolt","doi":"10.1186/s13046-025-03551-z","DOIUrl":"10.1186/s13046-025-03551-z","url":null,"abstract":"<p><strong>Background: </strong>To spatially characterize the single-cell tumor microenvironment (TME) of salivary gland carcinomas (SGC) and identify prognostic biomarkers.</p><p><strong>Methods: </strong>SGC, including salivary duct carcinomas (SDC), acinic cell, mucoepidermoid, and secretory carcinomas, were analyzed using a 13-marker imaging mass cytometry panel. Multichannel image data from 54 primary cases and nodal metastases were processed to generate single-cell datasets. Cell phenotypes (tumor cells, cancer-associated fibroblasts (CAFs), endothelia, immune cells) were classified using a validated CAF algorithm, followed by spatial analysis and clinicopathological correlation. Clinicopathological results were validated using a previously published independent bulk RNA-sequencing (RNA-seq) cohort of n = 67 SDC cases. Spatial transcriptomics data of three SDC cases was leveraged to understand the molecular mechanisms of spatial interactions.</p><p><strong>Results: </strong>Among 509,364 cells, SDC exhibited the highest fractions of Collagen- and matrix-CAFs (mCAFs). Acinic cell carcinomas (ACC) showed enriched CD4<sup>+</sup>/CD8<sup>+</sup> T cells and antigen-presenting CAFs (apCAFs), indicating strong immune infiltration. A spatially defined cellular neighborhood (CN8) of mCAFs and endothelia was elevated in SDC, with higher CAF infiltration in androgen receptor (AR)<sub>high</sub> versus AR<sub>low</sub> SDC. Elevated mCAF frequency and CN8 were significantly associated with reduced recurrence-free probability (RFP) and distant control rates (DCR) in SDC. Additionally, higher mCAF frequencies were an independent prognostic factor for decreased RFP and DCR in Cox regression analysis. The association between mCAFs and a decreased RFP as well as recurrence-free survival was confirmed with previously published RNA-seq data using an mCAF signature. Spatial transcriptomics confirmed enrichment of metastasis-associated gene signatures as well as platelet-derived growth factor and insulin-like growth factor pathways within mCAF<sup>high</sup>endothelia<sup>high</sup> tumor niches indicating that the latter may be involved in mCAF-endothelia crosstalk.</p><p><strong>Conclusion: </strong>SDC are characterized by Collagen-/mCAF-rich microenvironments and mCAF-endothelial spatial interactions that are linked to metastasis. ACC display pronounced immune infiltration, suggesting its potential for immunotherapy. mCAFs in SDC emerge as prognostic biomarkers and therapeutic targets, highlighting the importance of targeting CAF-driven metastasis in future treatments. This study provides insights into the biology of SGC and identifies novel prognostic markers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"288"},"PeriodicalIF":12.8,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145287365","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":"A novel lncRNA-mediated signaling axis governs cancer stemness and splicing reprogramming in hepatocellular carcinoma with therapeutic potential.","authors":"Ke Si, Lantian Zhang, Zehang Jiang, Zhiyong Wu, Zhanying Wu, Yubin Chen, Weifei Liang, Xiaoren Zhang, Wenliang Zhang","doi":"10.1186/s13046-025-03546-w","DOIUrl":"10.1186/s13046-025-03546-w","url":null,"abstract":"<p><strong>Background: </strong>Aberrant alternative splicing (AS) contributes to cancer stemness and progression in hepatocellular carcinoma (HCC). However, the regulatory roles of long noncoding RNAs (lncRNAs) in linking AS dysregulation to tumor stemness remain elusive.</p><p><strong>Methods: </strong>We performed integrated bulk and single-cell RNA-Seq analyses combined with functional assays to identify key lncRNAs associated with splicing regulation and cancer stemness in HCC. Mechanistic studies were conducted to elucidate the molecular interplay between lncRNAs, splicing factors, and transcriptional regulators. Drug sensitivity assays were used to evaluate therapeutic potential.</p><p><strong>Results: </strong>Global analysis revealed increased splicing regulator activity during hepatocellular carcinoma (HCC) progression, which correlated with poor prognosis. This splicing dysregulation led us to identify 28 lncRNAs that connect aberrant splicing with cancer stemness. Among these, RAB30-DT was significantly overexpressed in malignant epithelial cells and associated with advanced tumor stage, stemness features, genomic instability, and poor patient prognosis. Functional assays demonstrated that RAB30-DT promotes proliferation, migration, invasion, colony and sphere formation in vitro, and tumor growth in vivo. Mechanistically, RAB30-DT is transcriptionally activated by CREB1 and directly binds and stabilizes the splicing kinase SRPK1, facilitating its nuclear localization. This interaction broadly reshapes the AS landscape, including splicing of the cell cycle regulator CDCA7, to drive tumor stemness and malignancy. Importantly, pharmacological disruption of the CREB1-RAB30-DT-SRPK1 axis sensitizes HCC cells to targeted therapies.</p><p><strong>Conclusions: </strong>Our study reveals a novel lncRNA-mediated signaling axis that integrates transcriptional regulation and splicing reprogramming to sustain cancer stemness and progression in HCC. Targeting this axis offers promising therapeutic opportunities for HCC treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"287"},"PeriodicalIF":12.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12512555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259795","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":"The cGAS‒STING pathway in colorectal cancer: bridging innate immunity and therapeutic strategies.","authors":"Wen-Jing Li, Guang-Hui Dong, Yao Bi, You-Yan Han, Long-Long Sun, Tong Wang, Zhen-Hua Lin, Xiang-Shan Ren","doi":"10.1186/s13046-025-03544-y","DOIUrl":"10.1186/s13046-025-03544-y","url":null,"abstract":"<p><p>Colorectal cancer (CRC) continues to be a predominant cause of cancer-related mortality worldwide, with existing therapies constrained by systemic toxicity, resistance, and inadequate tumor targeting. While immunotherapy has potential in specific CRC subtypes, its overall effectiveness is still limited. The cyclic GMP‒AMP synthase-stimulator of interferon genes (cGAS‒STING) pathway, an essential cytosolic DNA sensor that facilitates innate immune responses, has surfaced as a prospective target for cancer immunotherapy. Recent studies have demonstrated that it plays dual roles in CRC: on the one hand, it triggers antitumor immune responses, while on the other hand, it promotes intestinal inflammation. Accurate delivery of STING agonists made feasible by developments in nanotechnology offers novel ways to modify the TME and overcome resistance. The current understanding of the activation and function of the cGAS-STING pathway in CRC, its impact on the TME, and recent developments in STING-targeted therapeutic approaches, comprising monotherapy and combination strategies with chemotherapy, radiotherapy, and immune checkpoint inhibitors, is summarized in this review. We also review new nanomedicine approaches designed to increase STING activation. Understanding the complex roles of cGAS-STING in CRC could help guide the development of next-generation immunotherapies with improved selectivity and efficacy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"286"},"PeriodicalIF":12.8,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253274","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}
Yuan Fang, Yunru Gu, Tingting Xu, Peng Wang, Xi Wu, Haoyang Shen, Yangyue Xu, Zixiang Xu, Lei Cao, Xiao Li, Hao Wu, Yongqian Shu, Pei Ma
{"title":"SENP1 drives glycolysis and cisplatin resistance in gastric cancer via desumoylating ENO1.","authors":"Yuan Fang, Yunru Gu, Tingting Xu, Peng Wang, Xi Wu, Haoyang Shen, Yangyue Xu, Zixiang Xu, Lei Cao, Xiao Li, Hao Wu, Yongqian Shu, Pei Ma","doi":"10.1186/s13046-025-03543-z","DOIUrl":"10.1186/s13046-025-03543-z","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer remains a leading cause of cancer-related mortality in world, with advanced-stage patients facing poor prognosis despite emerging therapies. SUMOylation modification is a major post-translation modification, which is essential for cellular behaviors. However, the potential function of SUMOylation in gastric cancer (GC) and the underlying molecular mechanisms remain unclear.</p><p><strong>Methods: </strong>In our study, a bioinformatics analysis was conducted to screen potential regulators within the SUMO-Specific Peptidase (SENP) family in GC. In vitro functional experiments including CCK8, colony formation, transwell assay, sphere formation, Glycolytic flux, ECAR and OCR and several animal models including GC xenografts, organoids and lung metastasis models were employed to ascertain the role of SENP1 in GC progression and metastasis. Mass spectrometry analysis, coimmunoprecipitation and immunofluorescence staining were performed to elucidate the mechanisms by which SENP1 functions in GC cells.</p><p><strong>Results: </strong>We identified that SENP1 was upregulated in GC tissues and correlated with a poor prognosis. Multiple functional experiments demonstrated that SENP1 promotes the proliferation, migration, stemness and glycolysis of GC cells. Mechanistically, SENP1 binds to α-enolase (ENO1) and deSUMOylates the SUMO sites (K256, K394) of SUMO2-modified ENO1, enhancing ENO1 stability and drive gastric tumorigenesis. Meanwhile, SENP1 inhibitor Momordin Ιc (Mc) in combination with cisplatin has a synergistic effect on gastric tumor growth in vitro and in vivo.</p><p><strong>Conclusion: </strong>SENP1 facilitates gastric cancer progression by metabolic reprogramming. Targeting SENP1 with Momordin Ic is a novel therapeutic approach for GC patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"285"},"PeriodicalIF":12.8,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253208","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}
Marwah Al-Mathkour, Zheng Chen, Julio Poveda, Longlong Cao, Oliver G McDonald, Dunfa Peng, Mohammed Soutto, Zhibin Chen, Heng Lu, Yan Guo, Shria Kumar, Alexander Zaika, Silvia Giordano, Shoumin Zhu, Wael El-Rifai
{"title":"CDK1 drives SOX9-mediated chemotherapeutic resistance in gastric cancer.","authors":"Marwah Al-Mathkour, Zheng Chen, Julio Poveda, Longlong Cao, Oliver G McDonald, Dunfa Peng, Mohammed Soutto, Zhibin Chen, Heng Lu, Yan Guo, Shria Kumar, Alexander Zaika, Silvia Giordano, Shoumin Zhu, Wael El-Rifai","doi":"10.1186/s13046-025-03523-3","DOIUrl":"10.1186/s13046-025-03523-3","url":null,"abstract":"<p><strong>Background: </strong>Gastric carcinoma ranks as the fifth most common cause of cancer-related mortality globally. Chemoresistance remains a critical barrier to treatment efficacy, driving poor survival outcomes in gastric cancer patients. Cyclin-dependent kinase 1 (CDK1) is overexpressed in several malignancies. SOX9 transcription factor plays critical roles in gastric tumorigenesis and therapeutic resistance. This study identifies a CDK1-SOX9-BCL-xL signaling axis as an important mediator of chemoresistance in gastric cancer.</p><p><strong>Methods: </strong>Bioinformatics and computational approaches were used for analysis of human and mouse public and local data sets. Chromatin immunoprecipitation (ChIP), western blotting, quantitative PCR (qPCR), immunofluorescence, and immunohistochemistry assays were applied in the study. The study utilized a number of in vitro models including cell lines and patient-derived tumoroids. The in vivo models included patient-derived xenograft (PDX), the Tff1 knockout, and Cdk1 conditional knockout mouse models.</p><p><strong>Results: </strong>Our study identified concurrent overexpression of CDK1 and SOX9 in gastric cancer patients. Genetic knockdown and pharmacological inhibition of CDK1 suppressed SOX9 protein levels and transcriptional activity in vitro and in vivo. Mechanistically, CDK1 regulates SOX9 through a miR-145-dependent epigenetic axis: CDK1-mediated phosphorylation and activation of DNMT1 to drive methylation-dependent silencing of miR-145, thereby relieving miR-145's repression of SOX9. Strikingly, both CDK1 and SOX9 were upregulated in cisplatin-resistant gastric cancer cell lines. We further identified BCL-xL as a direct transcriptional target of SOX9, functionally mediating cisplatin resistance. CDK1 inhibition using dinaciclib re-sensitized resistant models to cisplatin by disrupting the CDK1-SOX9-BCL-xL pathway, underscoring its central role in chemoresistance. In PDX models, combining dinaciclib with cisplatin synergistically reduced tumor volume, and extended survival compared to monotherapies, highlighting the therapeutic potential.</p><p><strong>Conclusion: </strong>This study elucidates the epigenetic and transcriptional mechanisms driving the CDK1-SOX9-BCL-xL axis in gastric cancer chemoresistance. Pharmacological inhibition of CDK1 effectively disrupts this axis, restoring cisplatin sensitivity and suppressing tumor growth in gastric cancer models. The observed synergy between dinaciclib and cisplatin underscores a promising therapeutic strategy to overcome chemoresistance in gastric cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"284"},"PeriodicalIF":12.8,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12506374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253249","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":"Cancer-associated fibroblast-derived circKLHL24 drives perineural invasion in pancreatic cancer via dual regulation of the sec31a-CXCL12 axis.","authors":"Tingting Li, Rihua He, Qing Tian, Tianhao Huang, Honghui Jiang, Huimou Chen, Yuan Yuan, Yong Jiang, Shangyou Zheng, Chonghui Hu, Shizong Li, Guolin Li, Rufu Chen","doi":"10.1186/s13046-025-03489-2","DOIUrl":"10.1186/s13046-025-03489-2","url":null,"abstract":"<p><strong>Background: </strong>Cancer-associated fibroblasts (CAFs) are key drivers of neural invasion in pancreatic cancer, yet their regulatory mechanisms remain elusive.This study explores the role of circular RNAs (circRNAs) in CAFs and their involvement in regulating neural invasion in pancreatic cancer.</p><p><strong>Methods: </strong>CAF-derived circRNAs were identified through circRNA high-throughput sequencing and quantitative real-time PCR (qRT-PCR). The impact of CAF-derived circKLHL24 on perineural invasion (PNI) in tumor cells was evaluated both in vitro and in vivo. RNA sequencing, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were conducted to identify downstream targets and elucidate the underlying mechanism of circKLHL24 in PNI.</p><p><strong>Results: </strong>CircKLHL24 (hsa_circ_0001369), a CAF-specific circRNA, is associated with PNI and poor survival in advanced PDAC. Silencing or overexpressing circKLHL24 in CAFs altered the ability of CAFs to induce tumor cell invasion and nerve infiltration via chemokine (C-X-C Motif) ligand 12 (CXCL12). Mechanistically, first, circKLHL24 binds to the membrane protein Sec31A, inhibiting its ubiquitination and degradation, thereby enhancing CXCL12 secretion. Second, circKLHL24 acts as a sponge for miR-615-5p, relieving its suppression of CXCL12 mRNA and amplifying CXCL12 expression. Moreover, high circKLHL24 levels were positively correlated with elevated serum CXCL12 levels in PDAC and poor patient survival. Targeting circKLHL24 or neutralizing CXCL12 suppresses PDAC invasion and neuronal recruitment in nude mouse and KPC models.</p><p><strong>Conclusions: </strong>The circKLHL24/Sec31A/miR-615-5p/CXCL12 axis is critical for CAF-induced PNI in PDAC. Therefore, circKLHL24 could serve as a potential therapeutic target for PDAC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"281"},"PeriodicalIF":12.8,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245550","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}