Cellular Oncology最新文献

{"title":"Unraveling the impact of cancer-associated fibroblasts on lymphatic metastasis of head and neck squamous cell carcinoma.","authors":"Zunxuan Xie, Boyang Gao, Han Wu, Fang Zheng, Qinglong Song, Cangwei Liu, Ce Shi","doi":"10.1007/s13402-025-01141-x","DOIUrl":"10.1007/s13402-025-01141-x","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) is characterized by a high incidence of lymphatic metastasis and poor clinical prognosis. Cancer-associated fibroblasts (CAFs), as major component of the tumor stroma, play pivotal roles in shaping the tumor microenvironment. With recent advances of single-cell omics and spatial transcriptomics, increasing evidence has revealed the phenotypic and functional heterogeneity of CAFs and their dynamic interactions with both tumor and stromal cells. These interactions contribute significantly to lymphatic metastasis through promoting lymphangiogenesis, remodeling the extracellular matrix (ECM), and modulating immune responses. Despite the growing recognition of CAFs as key mediators of metastasis, the precise mechanisms through which CAFs drive lymphatic spread in HNSCC remain largely unknown. This gap hampers the development of effective therapeutic strategies specifically targeting CAF-driven lymphatic dissemination. This review comprehensively summarizes the current knowledge on the mechanistic roles of CAFs in lymphatic metastasis in HNSCC, encompassing lymphangiogenesis, pre-metastatic niche formation, lymph node metastasis (LNM), and extranodal extension (ENE). Furthermore, we discuss emerging therapeutic strategies targeting CAFs in other malignant tumors and their translational potential implications for mitigating lymphatic metastasis in HNSCC. Understanding the complex interactions between CAFs and the lymphatic metastatic cascade may provide new opportunities for developing targeted interventions to improve clinical outcomes in HNSCC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"6"},"PeriodicalIF":4.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12748323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organoid-based drug screening identifies homoharringtonine as a therapeutic agent for anaplastic thyroid cancer via TFEB-mediated lysosomal dysfunction.","authors":"Xinyue Zhang, Zhihui Li, Jiaye Liu, Rui Huang","doi":"10.1007/s13402-025-01132-y","DOIUrl":"10.1007/s13402-025-01132-y","url":null,"abstract":"<p><strong>Purpose: </strong>Anaplastic thyroid cancer (ATC) is a rare but aggressive malignancy with unmet clinical needs for novel therapeutic agents. Most prior studies have relied on limited ATC cell lines, which fail to recapitulate tumor heterogeneity. This study aimed to discover novel agent for ATC via patient-derived organoid (PDO)-based drug screening and investigate the underlying therapeutic mechanism.</p><p><strong>Methods: </strong>Drug screening was performed on ATC organoids using a drug library of stem cell differentiation compounds. RNA-sequencing identified pathway-level mechanisms, while structure-based molecular docking prioritized target proteins.</p><p><strong>Results: </strong>Using a library of stem cell differentiation compounds, we identified homoharringtonine (HHT) as a potent inhibitor for ATC growth in vitro and in vivo. Mechanistically, this effect was mediated by lysosomal dysfunction, which blocked autophagosome-lysosome fusion and triggered cytotoxicity. Furthermore, HHT exhibited high affinity for the PI3K p110 subunit, activating the PI3K-AKT-mTOR pathway to phosphorylate transcription factor EB, retaining it in the cytoplasm and thereby inhibiting lysosomal biogenesis.</p><p><strong>Conclusion: </strong>Our study demonstrates the utility of cancer organoids in drug discovery and identifies HHT as a promising therapeuticagent for ATC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"5"},"PeriodicalIF":4.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12748095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis in hematological malignancies: molecular mechanisms and therapeutic potential.","authors":"Jiaxi Liu, Rui Liu, Jiyu Miao, Aili He","doi":"10.1007/s13402-025-01142-w","DOIUrl":"10.1007/s13402-025-01142-w","url":null,"abstract":"<p><p>Ferroptosis, an iron-dependent form of regulated cell death characterized by overwhelming accumulation of lipid peroxidation, has emerged as a prominent area of interest in cancer research. Its underlying mechanisms are complex, and the high heterogeneity of hematologic malignancies adds additional challenges. Unlike solid cancers, hematologic malignancies lack fixed tissue architecture and exist within the dynamic bone marrow microenvironment, where iron metabolism, redox balance, and lipid remodeling are uniquely regulated. These differences create distinct metabolic vulnerabilities-particularly in iron and polyunsaturated fatty acid metabolism-that may render hematologic cancer cells more sensitive to ferroptotic stress. Given these unique features, a systematic understanding of ferroptosis in hematologic malignancies is critical for both elucidating disease mechanisms and exploring novel therapeutic strategies. This review summarizes the current understanding of ferroptosis in the pathogenesis and therapeutic resistance of hematologic malignancies, highlighting its mechanistic diversity across leukemia, lymphoma, and multiple myeloma. We also discuss emerging therapeutic strategies that exploit ferroptosis and outline key challenges and future directions for translating ferroptosis-based interventions into clinical practice.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"10"},"PeriodicalIF":4.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12748143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM47-facilitated PLK1 stabilization promotes the proliferation of liver cancer cells.","authors":"Tao Xie, Xiaoqi Fan, Tian Yu, Qing Zhu, Qi Zhang, Na Li, Tao Wang, Yisong Qian, Keyu Deng, Hongbo Xin, Yong Li, Xuan Huang","doi":"10.1007/s13402-025-01130-0","DOIUrl":"10.1007/s13402-025-01130-0","url":null,"abstract":"<p><p>BACKGROUND: Liver cancer (LC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic options for advanced-stage disease. While tripartite motif-containing 47 (TRIM47), a typical E3 ubiquitin ligase, has been implicated in cancer progression, its precise role in LC pathogenesis remains unclear. METHODS: TRIM47 expression in hepatocellular carcinoma (HCC) tissues was analyzed through public databases. Functional assays, including TRIM47 knockdown and overexpression experiments, were performed to investigate its impact on cell proliferation, apoptosis and the cell cycle both in vitro and in vivo. The investigation was conducted using a combination of methodologies, including yeast-two hybrid screening, ubiquitination assays, and signaling pathway analyses, to elucidate the underlying mechanisms. In addition, rescue assays were performed to validate the effect of TRIM47-PLK1 axis on LC growth. RESULTS: TRIM47 was significantly elevated in HCC tissues and positively correlated with advanced clinical stage and poor overall survival. Functionally, TRIM47 knockdown suppressed LC cell growth, while its overexpression promoted tumor proliferation. Furthermore, TRIM47 facilitates cell cycle progression by alleviating G2/M phase arrest and inhibits apoptosis in LC cells. Mechanistically, TRIM47 catalyzes K63-linked ubiquitination of polo-like kinase 1 (PLK1), leading to its stabilization and subsequent activation of the NF-κB and MAPK pathways. Clinical validation confirmed a significant positive correlation between TRIM47 and PLK1 expression in human HCC specimens. Importantly, pharmacological inhibition of PLK1 effectively abrogated TRIM47-driven tumor growth in xenograft models. CONCLUSION: This study identifies TRIM47 as a critical regulator of LC progression through PLK1 stabilization and proposes the TRIM47-PLK1 axis as a potential therapeutic target for LC treatment. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"7"},"PeriodicalIF":4.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12748135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decitabine promotes degradation of DNMT1 and EZH2 via the ubiquitination pathway and inhibits colorectal cancer progression.","authors":"Xiao-Mei Peng, Xin-Peng Shi, Han Chen, Lu-Yang Cao, Hao-Jian Zuo, Jie-Qiong Guo, Nan Jiang, Xiao-Yong Luo","doi":"10.1007/s13402-025-01136-8","DOIUrl":"10.1007/s13402-025-01136-8","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to investigate the role of DNMT1 in CRC progression and its regulatory relationship with TRAF6 and EZH2.</p><p><strong>Methods: </strong>DNMT1 expression was analyzed in CRC tissues and cell lines using public databases and experimental techniques, including Western blot and qRT-PCR. Functional assays, such as colony formation, transwell migration/invasion, and cell cycle analysis, were performed to assess the role of DNMT1 in CRC cell proliferation and metastasis. Mechanistic studies, including cycloheximide (CHX) chase assays, ubiquitination assays, and co-immunoprecipitation (Co-IP), were conducted to explore the regulation of DNMT1 stability and its effects on EZH2 protein stability. The regulatory axis was further validated using methylation-specific PCR (MSP), dual-luciferase assays, and immunohistochemistry (IHC) in CRC patient tissues.</p><p><strong>Results: </strong>DNMT1 was significantly overexpressed in CRC tissues and cell lines, correlating with enhanced cell proliferation, migration, and invasion Mechanistically, DNMT1 is associated with CRC cell proliferation and regulate this process via upregulating cyclins D1/E2 and accelerating G1/S phase transition. Decitabine, a DNA methyltransferase inhibitor, induced DNMT1 degradation via the ubiquitin-proteasome pathway, with TRAF6 identified as a key E3 ubiquitin ligase mediating this process. TRAF6 was downregulated in CRC tissues and inversely correlated with DNMT1 expression. DNMT1 suppressed TRAF6 expression through promoter hypermethylation, forming a negative feedback loop. Additionally, DNMT1 stabilized EZH2 by inhibiting TRAF6-mediated ubiquitination, thereby enhancing EZH2-dependent oncogenic signaling. Functional experiments demonstrated that EZH2 was essential for DNMT1-mediated CRC progression.</p><p><strong>Conclusion: </strong>This study reveals a novel Decitabine-TRAF6-DNMT1-TRAF6-EZH2 regulatory axis in CRC. Decitabine has dual effects, suggesting a new therapy.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"9"},"PeriodicalIF":4.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12748097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The oncogenic potential of YAP requires Y357 phosphorylation in cholangiocytes but not in hepatocytes.","authors":"Muhammed Dogukan Aksu, Jayla T Millender, Chantal E McCabe, Ryan D Watkins, Jennifer A Yonkus, EeeLN H Buckarma, Nathan W Werneburg, Daniel R O'Brien, Rondell P Graham, Gregory J Gores, Rory L Smoot, Caitlin B Conboy","doi":"10.1007/s13402-025-01133-x","DOIUrl":"10.1007/s13402-025-01133-x","url":null,"abstract":"<p><p>PURPOSE: The transcriptional cofactor yes-associated protein (YAP) is activated in primary liver cancers (PLCs). YAP is canonically inhibited through serine 127 (S127) phosphorylation via the Hippo pathway but activated by phosphorylation at tyrosine 357 (Y357) by SRC family kinases. Due to liver plasticity, PLCs can originate from different cell types. However, it is unknown whether YAP activation favors tumorigenesis from specific cells of origin or promotes lineage commitment during tumorigenesis. This study investigates how YAP Y357 phosphorylation influences tumor phenotype and cell of origin. METHODS: C57BL/6 mice underwent biliary transfection with myr-AKT and YAP S127A (YAP-S) or YAP S127A/Y357F (YAP-SY). RNA sequencing and pathway analysis were performed on tumors. To determine the cell of origin, tumors were generated in lineage-tracing mice by biliary transfection or hydrodynamic tail vein injection. Two tumor-derived cell lines were isolated and characterized. RESULTS: YAP-S mice developed more frequent intrahepatic cholangiocarcinoma (iCCA), whereas a shift to hepatocellular carcinoma (HCC) was identified in YAP-SY mice. Transcriptome analysis revealed differential activation of pathways linked to this phenotypic switch. Lineage tracing demonstrated iCCA originated from cholangiocytes and HCC from hepatocytes in the biliary transfection, whereas iCCA originated from hepatocytes in the hydrodynamic tail vein injection. Two novel, transplantable syngeneic cell lines with mixed HCC/iCCA features were established. Tumors and cell lines commonly exhibited differential TGF-β signaling. CONCLUSIONS: YAP Y357 phosphorylation modifies the tumor phenotype and the cell of origin in liver cancer models. Differential TGF-β signaling suggests a potential therapeutic avenue for iCCA and mixed tumors. CLINICAL TRIAL NUMBER: Not applicable. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"4"},"PeriodicalIF":4.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12738621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatoid adenocarcinoma of the stomach and non-hepatoid alpha-fetoprotein-producing gastric cancer exhibit a high degree of molecular similarity.","authors":"Liqiao Chen, Xuesong Yang, Peiyu Zhu, Han Bao, Yan Wu, Ke Ji, Ji Zhang, Xiaojiang Wu, Kai Zhou, Jieli Xu, Jiatian Tang, Anqiang Wang, Zhaode Bu","doi":"10.1007/s13402-025-01145-7","DOIUrl":"10.1007/s13402-025-01145-7","url":null,"abstract":"<p><strong>Background: </strong>There is currently no unified consensus on the diagnosis and treatment of hepatoid adenocarcinoma of the stomach (HAS) and non-hepatoid AFP-producing gastric cancer (AFPGC). This study aims to explore the molecular similarities between the two, providing a basis for the diagnosis and precision treatment of these patients.</p><p><strong>Methods: </strong>We retrospectively collected tumor tissues, adjacent tissues, and peripheral blood samples from 83 patients for whole-exome sequencing or transcriptome sequencing. Spearman correlation analysis, unsupervised clustering analysis and so on were performed to assess the similarity between different sample groups, explore the molecular features of non-hepatoid AFPGC and HAS, and compare their correlations.</p><p><strong>Results: </strong>All the patient groups shared high-frequency mutated genes such as TP53, LRP1B, MUC16, CSMD3, and FAT4. Copy number variation analysis revealed similarities in the copy number variations between the two patient groups. The majority of patients in both groups exhibited amplification of the CCNE1 or ERBB2. PCA analysis based on transcriptomic data showed a clear clustering trend within the HAS and non-hepatoid AFPGC subgroups, which was distinct from conventional gastric adenocarcinoma. Moreover, unsupervised clustering analysis indicated that the samples within the different subgroups of the two groups had similar transcriptional expression patterns. Finally, we identified a potential therapeutic target, FAT4. Mutations in FAT4 further affect transcriptional expression and prognosis in gastric cancer patients, as well as influence immune infiltration and the response to immune checkpoint blockade therapy.</p><p><strong>Conclusion: </strong>HAS and non-hepatoid AFPGC exhibit a high degree of similarity at both the genomic and transcriptomic levels.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"1"},"PeriodicalIF":4.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12722461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-infiltrating lymphocyte expansion protocols for adoptive cell therapy in cancer.","authors":"Daniel Tovar Manzano, Nabil Subhi-Issa, Alejandro Pereiro-Rodríguez, Igor Gregorio López Cade, María Mateos González, Miguel Fernández Arquero, Pedro Pérez Segura, Cristina Ujaldón Miró, Silvia Sánchez-Ramón, Alberto Ocaña, María Guzmán Fulgencio","doi":"10.1007/s13402-025-01112-2","DOIUrl":"10.1007/s13402-025-01112-2","url":null,"abstract":"<p><p>Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TILs) has emerged as an innovative strategy in cancer immunotherapy, especially in the treatment of solid tumors. This review provides a comprehensive analysis of current TILs expansion protocols, with a focus on strategies aimed at optimizing their performance, feasibility and functionality. The classical TILs expansion protocol is based on a two-step process: a rapid pre-expansion phase (Pre-REP), followed by a rapid expansion phase (REP), in which high concentrations of interleukin-2 (IL-2) are used. In recent years, various modifications have been incorporated into the protocol with the aim of improving its efficiency, including the use of alternative combinations of cytokines such as IL-7, IL-15, and IL-21, as well as the replacement of irradiated feeder cells or anti-CD3 antibodies with other strategies. Furthermore, advances such as the targeting of TILs specific to neoantigens, the development of CAR-TILs, the application of artificial intelligence, and the genetic modification of TILs have contributed to expanding both the applicability and efficacy of this therapy. The clinical success of Lifileucel with the recent FDA approval of underscore the translational potential of TILs-based therapies. However, significant challenges remain, including time and production costs. This review examines ongoing clinical trials and combination therapeutic strategies, such as the use of immune checkpoint inhibitors. As research progresses, optimization of TILs expansion protocols will be critical to improving clinical outcomes and broadening the applicability of this personalized immunotherapy in oncology.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1659-1675"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12698757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145539302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis delineates molecular signatures of spinal ependymal tumor.","authors":"Weihao Liu, Chao Ning, Xiaohan Geng, Bo Wang, Yaowu Zhang, Chong Wang, Yixiang Liu, Guanghao Zheng, Yongzhi Wang, Xinyu Wang, Dong Li, Wenqing Jia","doi":"10.1007/s13402-025-01122-0","DOIUrl":"10.1007/s13402-025-01122-0","url":null,"abstract":"<p><strong>Background: </strong>Spinal ependymal tumors are a diverse group of neoplasms encompassing four subtypes: spinal ependymoma (SP-EPN), spinal ependymoma, MYCN-amplification (SP-EPN-MYCN), spinal myxopapillary ependymoma (SP-MPE), and spinal subependymoma (SP-SE). However, the molecular differences among these subtypes remain largely unknown.</p><p><strong>Methods: </strong>Using an integrated multi-omics approach (whole-genome sequencing, RNA-seq, and mass spectrometry), we identified the distinct molecular characteristics of three subtypes except for SP-EPN-MYCN.</p><p><strong>Results: </strong>In SP-EPN, abnormal enrichment of ciliary signaling, particularly involving the MKS complex, was evident. SP-MPE exhibited significant dysregulation of mitochondrial metabolism, reflecting a metabolic profile aligned with the Warburg effect. SP-SE tumors showed enhanced activity of immune-related pathways, including interferon signaling and extracellular vesicle dynamics, suggesting a distinct tumor microenvironment.</p><p><strong>Conclusion: </strong>This pilot study identifies candidate molecular markers in a single-center spinal ependymal tumor cohort.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1987-2000"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12698791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulated NNMT sustains angiogenesis in clear cell renal cell carcinoma through activation of the SDF-1/CXCR4-ERK-CCL20 axis.","authors":"Wenfu Zhang, Yang Yu, Bo Geng, Xin Shao, Wei Zhang, Zhuolun Li, Yunhui Chan, Nan Zhang, Jinpeng Wang, Yunfeng Nan, Kaifeng Wang, Meng Dong, Weikang Ma, Bosen You, Xuedong Li, Enyang Zhao","doi":"10.1007/s13402-025-01115-z","DOIUrl":"10.1007/s13402-025-01115-z","url":null,"abstract":"<p><p>BACKGROUND: Nicotinamide N-methyltransferase (NNMT) is involved in the development of several cancers. Tumor stem cells are present in various cancers and are linked to treatment resistance, tumor recurrence, and metastasis. However, the role of NNMT in regulating the stemness characteristics of clear cell renal cell carcinoma (ccRCC) is not yet fully understood. METHODS: NNMT expression was identified as differentially expressed through the analysis of TCGA and GEO datasets (GSE105261 and GSE66272). Functional significance was explored using xenograft models. We performed qPCR, western blot, enzyme-linked immunosorbent assay (ELISA) and additional assays to examine the effects of NNMT on ccRCC stem cells. The potential molecular mechanism of ccRCC stem cells in promoting angiogenesis was investigated through RNA-seq analysis. The expression of C-C motif chemokine ligand 20 (CCL20) was validated through western blot and ELISA analyses. Regulation of angiogenesis was assessed using tube formation assays and Matrigel plug assays. RESULTS: NNMT was significantly upregulated in ccRCC tumor tissues and impaired the prognosis in ccRCC patients. In vivo studies revealed that NNMT depletion significantly inhibited tumor growth, whereas increased NNMT levels enhanced tumor progression. Additionally, NNMT enhanced the stemness characteristics of ccRCC cells and maintained C-X-C chemokine receptor type 4 (CXCR4) expression through the activation of Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation. Moreover, NNMT facilitated the recruitment and differentiation of ccRCC stem cells towards endothelial cells via the stromal cell–derived factor 1 (SDF-1)/CXCR4 axis, thereby promoting vessel function and tumor growth. CONCLUSION: NNMT functions as an oncogene, strengthening the stemness properties of ccRCC cells and sustaining angiogenesis. These results indicate that NNMT may be a viable therapeutic target and prognostic biomarker for ccRCC. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"1889-1901"},"PeriodicalIF":4.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12698800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}