Cellular Oncology最新文献

{"title":"CircBARD1 suppresses tumor progression driven by H3K18 lactylation-CCNA2 axis in human bladder cancer.","authors":"Zhenghui Hu, Nan Jiang, Bo Xie, Jiatong Zhou, Juntao Lin, Xianwu Chen, Xuejian Zhou, Yan Zhang, Mengjing Fan, Ning He, Xiaodong Jin, Feifan Wang","doi":"10.1007/s13402-026-01180-y","DOIUrl":"10.1007/s13402-026-01180-y","url":null,"abstract":"<p><p>BACKGROUND: Bladder cancer (BCa) represents the fourth most prevalent malignancy worldwide, characterized by unfavorable clinical outcomes. The functional significance and molecular mechanisms underlying circular RNAs in BCa pathogenesis require further investigation. This study reveals that circBARD1 suppresses histone lactylation-driven tumor progression by modulating ENO1 protein stability in bladder cancer. METHODS: Functional characterization of circBARD1 was performed through gain-of-function experiments in T24 and TCCSUP cell lines. RNA immunoprecipitation (RIP) and immunoprecipitation assays were employed to investigate circBARD1-ENO1 interactions. CUT&Tag and chromatin immunoprecipitation (ChIP) assays were conducted to examine H3K18 lactylation-mediated transcriptional regulation of CCNA2. RESULTS: CircBARD1 expression was significantly downregulated in bladder cancer tissues. Ectopic expression of circBARD1 inhibited malignant proliferation and migration capacities in BCa cell lines. Furthermore, circBARD1 demonstrated negative regulation of glycolytic flux and intracellular lactate accumulation. Mechanistic studies revealed that circBARD1 physically interacts with ENO1 protein, facilitating its ubiquitination-mediated proteasomal degradation mediated by FBXW7. This circBARD1/ENO1 regulatory axis attenuates tumor progression through suppression of H3K18 lactylation and subsequent downregulation of CCNA2 transcription. CONCLUSIONS: Our findings establish that circBARD1 functions as a tumor suppressor in bladder cancer by promoting ENO1 ubiquitination and degradation, thereby inhibiting histone lactylation-mediated oncogenesis. This study provides new insights into therapeutic targets for clinical management of bladder cancer. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147484832","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":"NUAK1 silencing enhances radiotherapy-induced ferroptosis in locally advanced rectal cancer by impairing Nrf2-driven transcription of GPX4.","authors":"Zhicheng Zhuang, Bingjie Guan, Ye Wang, Xinru Lin, Huajun Cai, Bin Chen, Shoufeng Li, Xing Liu, Jinfu Zhuang, Guoxian Guan","doi":"10.1007/s13402-026-01187-5","DOIUrl":"10.1007/s13402-026-01187-5","url":null,"abstract":"<p><p>PURPOSE: Radiotherapy resistance is a primary cause of treatment failure in locally advanced rectal cancer (LARC). Tumor cells can evade radiotherapy-induced ferroptosis by upregulating the antioxidant protein GPX4. NUAK1 is highly expressed in colorectal cancer and associated with poor prognosis, but its role in regulating radiosensitivity remains to be elucidated. METHODS: Radiosensitivity was assessed in vitro and in vivo using CCK-8 assays, clonogenic survival assays, and a nude mouse xenograft model. Lipid peroxidation levels were quantified via flow cytometry with C11-BODIPY probe and malondialdehyde (MDA) assay. Ferroptosis-specific mitochondrial morphology was examined by transmission electron microscopy. Nuclear translocation of Nrf2 was detected by nucleocytoplasmic separation experiments and Western blot, while GPX4 promoter and antioxidant response element (ARE) transcriptional activities were measured using dual-luciferase reporter assays. The contribution of ferroptosis was assessed using cell death inhibitors. The Nrf2-specific inhibitor ML385 was utilized to investigate the functional dependency between NUAK1 and Nrf2. Immunohistochemistry (IHC) was used to analyze the correlation between NUAK1 protein expression and radiotherapy response in LARC patients. RESULTS: NUAK1 knockdown significantly enhanced radiotherapy-induced ferroptosis and radiosensitivity, as evidenced by increased lipid peroxidation, altered mitochondrial morphology, and reduced clonogenic survival. Mechanically, NUAK1 deficiency impaired Nrf2 nuclear translocation and transcriptional activity after radiation, leading to downregulation of GPX4 expression. The Nrf2 inhibitor ML385 completely abrogated NUAK1 overexpression-induced GPX4 upregulation and radioprotection. Clinical sample analysis revealed that high NUAK1 expression was correlated with radioresistance and poor tumor regression. CONCLUSION: This study is the first to elucidate the critical role of the NUAK1-Nrf2-GPX4 signaling axis in LARC radioresistance. These findings not only reveal a novel mechanism by which tumor cells evade radiotherapy-induced ferroptosis but also provide a potential biomarker and combination therapeutic target for overcoming clinical radioresistance. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13000069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479644","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":"B3GNT3 facilitates NFKB2 processing and non-canonical NF-κB activation to drive lung adenocarcinoma progression.","authors":"Ying Lin, Yao Zhang, Bo Yu, Jialei Wang, Zheng Wu, Huijie Wang","doi":"10.1007/s13402-026-01192-8","DOIUrl":"10.1007/s13402-026-01192-8","url":null,"abstract":"<p><p>PURPOSE: Aberrant glycosylation is implicated in tumor progression. However, the role of β-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) in non-small cell lung cancer (NSCLC) remains poorly understood. METHODS: Public cancer databases and clinical specimens were analyzed to evaluate the expression pattern and prognostic value of B3GNT3 in NSCLC. Gain- and loss-of-function approaches were employed to investigate the effects of B3GNT3 on lung adenocarcinoma (LUAD) cell proliferation, cell cycle progression, invasion, anoikis resistance in vitro, and tumor growth in vivo. Transcriptomic profiling identified B3GNT3-associated signaling pathways. Protein-protein interactions were examined using immunoprecipitation coupled with mass spectrometry and co-immunoprecipitation assays, followed by functional validation through genetic ablation studies. A catalytic inactive mutant of B3GNT3 was generated to assess whether its oncogenic function depends on glycosyltransferase activity. RESULTS: B3GNT3 was frequently upregulated in NSCLC tissues and significantly correlated with poor prognosis. Functional studies demonstrated that B3GNT3 promoted LUAD cell proliferation, anchorage-independent growth, invasion, anoikis resistance, and xenograft tumor growth. Transcriptomic analyses linked B3GNT3 to epithelial-mesenchymal transition (EMT) and NF-κB signaling. Mechanistically, B3GNT3 physically interacted with NFKB2, facilitating p100 phosphorylation, processing into p52, and nuclear accumulation, thereby activating non-canonical NF-κB signaling. Genetic ablation of NFKB2 markedly reversed the oncogenic effects of B3GNT3, including altered cell cycle gene expression, EMT-associated gene expressions, enhanced invasive capacity, anoikis resistance, and accelerated tumor growth. Importantly, catalytic inactivation of B3GNT3 did not impair its ability to interact with NFKB2 or to promote p100 processing and EMT-related phenotypes, indicating that its tumor-promoting function is largely independent of glycosyltransferase activity. CONCLUSION: Our study identifies B3GNT3 as a novel oncogenic driver in LUAD and reveals a B3GNT3-NFKB2 signaling axis that promotes tumor progression through non-canonical NF-κB activation in a catalysis-independent manner. These findings suggest that therapeutic strategies targeting B3GNT3-mediated signaling interactions, rather than enzymatic activity alone, may represent a potential approach for LUAD treatment. CLINICAL TRIAL REGISTRATION: Not applicable. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12992861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467178","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":"Distinct clinical and genomic profiles of braf mutation subtypes in Chinese colorectal cancer: a retrospective cohort study with cross-population validation.","authors":"Wentao Yang, Yi Duan, Xiao Huang, Wang Song, Jingyi Qian, Yiwei Zeng, TianAn Guo, Yunyu Wu, Hong Li, Xuan Zou, Ye Xu","doi":"10.1007/s13402-026-01185-7","DOIUrl":"10.1007/s13402-026-01185-7","url":null,"abstract":"<p><p>PURPOSE: To characterize the clinicogenomic features, prognostic significance and therapeutic implications of BRAF mutation subtypes in Chinese colorectal cancer (CRC) patients. METHODS: We performed integrated genomic and clinical analyses on 146 BRAF-mutant colorectal cancers identified within a cohort of 2,446 consecutive CRC patients at Fudan University Shanghai Cancer Center (FUSCC) encompassing surgical, neoadjuvant, and advanced disease. Targeted sequencing defined genomic profiles, benchmarking against the western cohorts (TCGA/MSKCC). Clinical outcomes including overall survival (OS), metastasis site, and treatment response were assessed. Isogenic cell line models validated functional impacts of BRAF variants. RESULTS: The FUSCC cohort exhibited a lower overall frequency of BRAF mutations, with V600E accounting for 54.1% of BRAF mutant cases. Compared with the western cohorts, Chinese patients harboring BRAF mutations were younger at diagnosis, presented with fewer metastatic cases, and displayed distinct co-mutation patterns, notably a higher prevalence of BRAFV600E-TP53 co-mutations which predicted poor prognosis. The BRAFV600E subtype was associated with significantly worse OS, an increased risk of peritoneal metastasis, female, advanced disease stage, and poor tumor differentiation compared with BRAFnon−V600E patients. In contrast, non-V600E tumors exhibited a higher tumor mutational burden. In vitro functional assays further confirmed that BRAFV600E mutant cells possessed enhanced proliferative and invasive capacities. Clinically, patients with BRAFV600E mutations demonstrated inferior responses to first-line therapy compared with non-V600E cases (ORR: 21.1% vs. 63.2%; P < 0.01), particularly in those receiving bevacizumab-based regimens. CONCLUSION: BRAFV600E defines an aggressive CRC subset in Chinese patients with distinct genomic and clinical features, supporting the need for population-tailored precision oncology strategies in Asian populations. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12992859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467110","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":"Single-cell transcriptomic mapping of patient-derived primary liver cancer organoids reveals molecular subtypes and guides precision drug targeting.","authors":"Shipeng Dai, Jian Wu, Yue Chai, Zhouxiao Li, Yuchen Xie, Hongyu Wang, Ziyuan Liu, Yanshu He, Hengsong Cao, Weiwei Tang, Jintao Xu, Zongkang Zhang, Yongxiang Xia, Xuehao Wang, Li Liu, Xinyi Xia, Yun Gao","doi":"10.1007/s13402-026-01190-w","DOIUrl":"10.1007/s13402-026-01190-w","url":null,"abstract":"<p><p>BACKGROUND: Current liver cancer research lacks reliable in vitro models that replicate tumor pathophysiology. This study establishes primary liver cancer (PLC) organoids from three major subtypes—hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (CHC)—to enable precise diagnostics and personalized therapies through comprehensive genomic profiling. METHODS: Organoid cultures were generated from 11 PLC patients (5 HCC, 3 ICC, 3 CHC). Whole exome sequencing (WES), RNA-seq, and single-cell RNA-seq (scRNA-seq) were performed to analyze molecular differences. Drug screening targeting subtype-specific pathways was conducted to validate sequencing findings. RESULTS: WES and RNA-seq confirmed that organoids retained parental tumor genetics and heterogeneity, distinct from paracancerous tissues. scRNA-seq revealed distinct cell populations in HCC, ICC, and CHC organoids. Lipid metabolism was enriched in HCC organoids; tumor migration pathways were upregulated in ICC organoids; and mitochondrial function was enhanced in CHC organoids. Rosuvastatin inhibited HCC growth by targeting lipid metabolism, while pemigatinib reduced ICC malignancy by suppressing epithelial-mesenchymal transition. Regorafenib impaired mitochondrial function in CHC organoids, slowing progression. CONCLUSIONS: PLC-derived organoids serve as robust tools for biomarker discovery and drug screening. scRNA-seq elucidates inter- and intra-tumoral heterogeneity, offering insights for precision therapy in liver cancer. This model advances personalized treatment strategies for diverse PLC subtypes. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12992744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467097","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":"NR2F2/AGAP2 axis: regulating lipid synthesis to drive AML progression via AMPKα/ACC pathway.","authors":"Qi Xin, Henan Zhang, Zheng Zhao, Gang Xu, Jihong Zhang","doi":"10.1007/s13402-026-01184-8","DOIUrl":"10.1007/s13402-026-01184-8","url":null,"abstract":"<p><p>PURPOSE: This study aims to investigate the role of AGAP2 in acute myeloid leukemia (AML), particularly its involvement in lipid metabolic reprogramming and AML progression, and to explore the underlying regulatory mechanisms. METHODS: AGAP2 expression was analyzed in CD34⁺ cells from AML patients stratified by cytogenetic risk. Functional assays, including knockdown and overexpression of AGAP2, were performed in KG-1 and HL-60 AML cell lines to assess effects on proliferation, apoptosis, differentiation, and lipid metabolism. mRNA sequencing and KEGG pathway analysis were used to identify relevant signaling pathways. Lipid accumulation was evaluated via Filipin III staining. The AMPK pathway activator GSK621 was applied to examine lipid deposition. In vivo tumor growth and survival were studied in a mouse model, and bone marrow infiltration of CD45⁺ cells was analyzed. The transcriptional regulation of AGAP2 by NR2F2 was assessed through promoter binding and functional rescue experiments. RESULTS: AGAP2 was highly expressed in CD34⁺ cells from AML patients, with higher levels in the poor-risk group compared to favorable- and intermediate-risk groups. Knockdown of AGAP2 induced apoptosis and differentiation, while its overexpression promoted cell proliferation. KEGG analysis indicated enrichment of differentially expressed genes in the AMPK pathway. AGAP2 was found to inhibit AMPK/ACC pathway activation. Overexpression of AGAP2 increased lipid deposition whereas GSK621 treatment reversed it. In vivo, AGAP2 knockdown suppressed tumor growth, improved survival, and reduced CD45⁺ cell infiltration in bone marrow. Furthermore, NR2F2 bound to the AGAP2 promoter and suppressed its transcription. NR2F2 overexpression reduced lipid accumulation, an effect reversed by AGAP2 overexpression. CONCLUSION: AGAP2 promotes lipid deposition and AML progression by inhibiting the AMPKα/ACC pathway. NR2F2 acts as a transcriptional repressor of AGAP2, thereby attenuating AML development. These findings reveal a novel NR2F2/AGAP2/AMPK/ACC regulatory axis in AML, highlighting potential therapeutic targets for lipid metabolism-based interventions in leukemia. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12992729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147467123","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":"Hepatocellular carcinoma and vitamin D metabolism: novel targets and therapeutic strategies.","authors":"Hanlin Gao, Li He, Zhi Chen, Gang Wang","doi":"10.1007/s13402-026-01183-9","DOIUrl":"10.1007/s13402-026-01183-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. While age-standardized incidence and mortality have declined in some regions, the overall global burden continues to increase because of population aging and persistent etiologic factors. Curative options are limited to selected patients, and systemic therapies provide modest long-term benefit. Beyond its canonical role in calcium-phosphate homeostasis, vitamin D signals through the nuclear vitamin D receptor (VDR) to modulate immunity, oxidative stress, fibrosis, and cellular metabolism. In HCC, this axis is frequently dysregulated, including downregulation of CYP2R1, reduced CYP27B1 activity, upregulation of CYP24A1, and VDR dysfunction, which together blunt the antitumor actions of vitamin D and are linked to inflammation, aberrant lipogenesis, and immune evasion. Here, we summarize mechanisms by which vitamin D impacts key oncogenic pathways in HCC, including PI3K/AKT/mTOR, IL-6/STAT3, NF-κB, and TGF-β/SMAD, and highlight downstream nodes such as SREBP-1 and TXNIP as potential therapeutic targets. We also discuss emerging strategies to restore vitamin D signaling, such as CYP24A1 inhibition, next-generation vitamin D analogs, and VDR-biased agonists, to facilitate clinical translation and drug development.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12979787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430913","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":"Strategies to target PD-1/PD-L1 in the tumor microenvironment.","authors":"Yulan Kui, Fan Tong, Ruiguang Zhang, Xiaorong Dong, Jian Wang","doi":"10.1007/s13402-026-01181-x","DOIUrl":"10.1007/s13402-026-01181-x","url":null,"abstract":"<p><p>In recent years, cancer immunotherapy has become one of the most important methods in cancer treatment, which can kill tumors by activating the immune system. The PD-1/PD-L1 immune checkpoint signaling pathway in the tumor microenvironment can impair T cell responses and thereby promote tumor immune escape. Blocking the PD-1/PD-L1 signaling pathway can enhance the antitumor immune response and improve the therapeutic effect. Anti-PD-1/PD-L1 antibodies have shown antitumor effects in clinical practice and are revolutionizing the field of cancer management. Recent studies have shown that the PD-1/PD-L1 pathway in the tumor microenvironment is finely regulated, and inhibition of the PD-1/PD-L1 signal by targeting its regulatory mechanism can activate the antitumor immune response and reverse the tumor immunosuppressive microenvironment. New strategies and drugs designed and developed for the PD-1/PD-L1 blockade have brought new hope for better treatment of tumors. CLINICAL TRIAL NUMBER: Not applicable. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12963217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353674","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":"Disconnect between in vitro and in vivo efficacy of the MPS1 inhibitor NTRC 0066-0 against glioblastoma.","authors":"Mark C de Gooijer, Daria M Fedorushkova, Ping Zhang, Levi C M Buil, Ceren H Çitirikkaya, Hilal Çolakoğlu, Ana Rita R Maia, Irena Bočkaj, Margarita Espitia-Ballestas, Laura E Kuil, Jos H Beijnen, Olaf van Tellingen","doi":"10.1007/s13402-026-01175-9","DOIUrl":"10.1007/s13402-026-01175-9","url":null,"abstract":"<p><p>PURPOSE: Glioblastoma (GBM) is the most common adult primary brain tumor for which new therapeutic strategies are desperately needed. Monopolar spindle 1 (MPS1) is a mitotic kinase that plays a pivotal role in the spindle assembly checkpoint (SAC). GBM appears to be dependent on SAC fidelity, as MPS1 is overexpressed in many GBM patients. Thus, inhibiting MPS1 seems a viable therapeutic strategy to enhance mitotic cell death by attenuating SAC fidelity. NTRC 0066-0 is an MPS1 inhibitor that combines low nanomolar potency with a relatively long on-target residence time. METHODS: We here investigate the potential of NTRC 0066-0 as monotherapy and in combination with chemo-radiation for treatment of GBM using various in vitro and orthotopic in vivo models. RESULTS: We show that NTRC 0066-0 efficiently induces GBM cell death in vitro, following continuous exposure with IC50s in the low nanomolar range. In vivo, we demonstrate that NTRC 0066-0 has a high brain penetration, although it is a substrate of the efflux transporter P-glycoprotein at the blood-brain barrier. However, despite using recipient Abcb1a/b; Abcg2−/− mice with superior brain penetration and administering NTRC 0066-0 using a dose-dense regimen, we did not observe antitumor efficacy against an orthotopic GBM mouse model, neither as monotherapy nor in combination with standard-of-care temozolomide chemotherapy and radiotherapy. CONCLUSION: These data indicate that developing MPS1 inhibitors for treatment of GBM will be challenging and would require further understanding of in vivo determinants of translating SAC inhibition to antitumor efficacy. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 2","pages":"46"},"PeriodicalIF":4.8,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12909347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200221","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":"Hippo signalling pathway mediates oncogenic properties of NAB2::STAT6 in solitary fibrous tumour.","authors":"Carmen Salguero-Aranda, Laura Lobo-Selma, Amparo Beltrán-Povea, Sergio Baute-González, Paula Gilabert-Prieto, Carmen Jordán-Perez, José Alberto Fernández-Juárez, Ana Teresa Amaral, René Rodríguez, Juan Díaz-Martín, Enrique de Álava","doi":"10.1007/s13402-026-01173-x","DOIUrl":"10.1007/s13402-026-01173-x","url":null,"abstract":"<p><p>PURPOSE: Solitary fibrous tumour (SFT) is a rare mesenchymal neoplasm molecularly defined by the NAB2::STAT6 gene fusion (GF), an aberrant transcriptional regulator whose functions beyond EGR1 activation remain incompletely understood. This study aimed to further elucidate the oncogenic role of NAB2::STAT6 and to identify potential therapeutic vulnerabilities. METHODS: Human mesenchymal stem cell–derived SFT models (SFT-MSCs) were generated via ectopic expression of NAB2::STAT6 and analysed by gene expression microarray to assess the impact of this fusion on the transcriptomic profile. Stable SFT-MSC clones were subjected to functional assays following YAP1/TAZ silencing via siRNAs or pharmacological inhibition with dasatinib. Transcriptomic profiling of 16 tumours was performed to investigate correlations between Hippo pathway and EGR1 transcriptional signatures. Nuclear YAP1/TAZ expression was assessed by immunohistochemistry (IHC) in 44 patient samples, and genomic structural variations (SVs) were analyzed in 8 SFT specimens through Optical Genome Mapping. RESULTS: NAB2::STAT6 ectopic expression led to Hippo pathway dysregulation and promoted a malignant phenotype, which was partially reversible upon YAP1/TAZ knockdown or dasatinib treatment. Total RNA-seq of SFT local cases confirmed transcriptional inactivation of Hippo signalling and revealed a network linking Hippo and EGR1 pathways. Stronger nuclear YAP1/TAZ staining was observed in relapsed SFT samples compared with primary tumors. The overall genomic stability precluded Hippo pathway deregulation via SVs in clinical samples. CONCLUSION: NAB2::STAT6 promotes SFT progression by inactivating the Hippo pathway, unveiling a potential targetable vulnerability and further expanding our understanding of NAB2::STAT6-driven oncogenesis. </p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 1","pages":"43"},"PeriodicalIF":4.8,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12891060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149266","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}