Oncogene最新文献

{"title":"m⁶A modification-dependent upregulation of WNT2 facilitates M2-like macrophage polarization and perpetuates malignant progression of nasopharyngeal carcinoma.","authors":"Qiling Tang, Lvyuan Li, Junshang Ge, Dan Wang, Hongke Qu, Jie Wu, Qian Wang, Zhouying Peng, Yongzhen Mo, Yumin Wang, Chunmei Fan, Qijia Yan, Pan Chen, He Huang, Wenjia Guo, Lei Shi, Zhaoyang Zeng, Wei Xiong","doi":"10.1038/s41388-025-03452-7","DOIUrl":"https://doi.org/10.1038/s41388-025-03452-7","url":null,"abstract":"<p><p>The development and progression of nasopharyngeal carcinoma (NPC) involves intricate interactions between tumor cells and other surrounding cells in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) play pivotal roles in the progression of NPC, but their interactions remain largely unexplored. In this study, we revealed that NPC promoted M2-like polarization of TAMs through enhanced synthesis and secretion of WNT2. These M2-type macrophages, in turn, significantly boosted the proliferation and metastasis of NPC. This vicious cycle perpetuated the malignant progression of NPC. Mechanistically, elevated m⁶A modification of WNT2 in NPC stabilized its mRNA and facilitated its protein expression, which is coordinately regulated by the m⁶A \"eraser\" ALKBH5 and the \"reader\" YTHDF1. NPC promoted M2-like polarization of macrophages by activating the FZD2/β-catenin signaling axis through paracrine WNT2. Furthermore, elevated WNT2 can also trigger the WNT/β-catenin signaling pathway in NPC cells through autocrine signaling, synergically contributing to NPC development. The research reveals that WNT2 is upregulated in an m⁶A modification-dependent manner and promotes M2-like macrophages polarization of TAMs and malignant progression of NPC. This discovery provides novel potential molecular markers and therapeutic targets for the diagnosis and treatment of NPC.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-translational modifications in DNA damage repair: mechanisms underlying temozolomide resistance in glioblastoma.","authors":"Yike Chen, Kaikai Ding, Shuyu Zheng, Songting Gao, Xiaohui Xu, Haijian Wu, Fengqi Zhou, Yongjie Wang, Jinfang Xu, Chun Wang, Chenhan Ling, Jing Xu, Lin Wang, Qun Wu, Georgios Giamas, Gao Chen, Jianmin Zhang, Chenggang Yi, Jianxiong Ji","doi":"10.1038/s41388-025-03454-5","DOIUrl":"https://doi.org/10.1038/s41388-025-03454-5","url":null,"abstract":"<p><p>Temozolomide (TMZ) resistance is one of the critical factors contributing to the poor prognosis of glioblastoma (GBM). As a first-line chemotherapeutic agent for GBM, TMZ exerts its cytotoxic effects through DNA alkylation. However, its therapeutic efficacy is significantly compromised by enhanced DNA damage repair (DDR) mechanisms in GBM cells. Although several DDR-targeting drugs have been developed, their clinical outcomes remain suboptimal. Post-translational modifications (PTMs) in GBM cells play a pivotal role in maintaining the genomic stability of DDR mechanisms, including methylguanine-DNA methyltransferase-mediated repair, DNA mismatch repair dysfunction, base excision repair, and double-strand break repair. This review focuses on elucidating the regulatory roles of PTMs in the intrinsic mechanisms underlying TMZ resistance in GBM. Furthermore, we explore the feasibility of enhancing TMZ-induced cytotoxicity by targeting PTM-related enzymatic to disrupt key steps in PTM-mediated DDR pathways. By integrating current preclinical insights and clinical challenges, this work highlights the potential of modulating PTM-driven networks as a novel therapeutic strategy to overcome TMZ resistance and improve treatment outcomes for GBM patients.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated loss-of-function mutations in KCNQ1 enhance Wnt/β-catenin signalling disrupting epithelial homeostasis.","authors":"Camille Berenguier, Xingyu Chen, Benoit Allegrini, Hélène Guizouarn, Franck Borgese, Catherine Etchebest, Olivier Soriani, Raphael Rapetti-Mauss","doi":"10.1038/s41388-025-03447-4","DOIUrl":"https://doi.org/10.1038/s41388-025-03447-4","url":null,"abstract":"<p><p>Ion channels are emerging as regulators of intracellular signalling pathway, yet the molecular mechanisms underlying this role remain poorly understood. KCNQ1, a potassium channel with tumour suppressor functions, restricts Wnt/β-catenin signalling, a pathway whose dysregulation, often driven by protein-altering mutations, is a hallmark of several epithelial cancers. Here, we identify loss-of-function (LOF) mutations in KCNQ1 across multiple epithelial cancers and elucidate their impact on Wnt/β-catenin signalling. Our findings reveal that cancer-associated KCNQ1-LOF mutations regulate the β-catenin pathway through a dual mechanism. First, they drive β-catenin transcriptional activity through triggering MET receptor, bypassing Frizzled/LRP6 receptor complex activation. Second, these mutations suppress the expression of key negative regulators of Wnt signalling, such as DKK-1, Wif-1 and NKD-1, leading to amplified pathway activation in response to Wnt ligand stimulation. This dysregulation disrupts epithelial homeostasis, as demonstrated by impaired crypt organization and increased proliferation in mouse colon-derived organoids. Together, these findings uncover an original mechanism linking KCNQ1 dysfunction to aberrant Wnt/β-catenin signalling, highlighting the role of ion channels in regulating epithelial signalling networks and tissue homeostasis.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erk1^R84H is an oncoprotein that causes hepatocellular carcinoma in mice and imposes a rigorous negative feedback loop.","authors":"Nadine Soudah, Alexey Baskin, Merav Darash-Yahana, Ilona Darlyuk-Saadon, Karina Smorodinsky-Atias, Tali Shalit, Wei-Ping Yu, Alon Savidor, Eli Pikarsky, David Engelberg","doi":"10.1038/s41388-025-03437-6","DOIUrl":"https://doi.org/10.1038/s41388-025-03437-6","url":null,"abstract":"<p><p>The receptor tyrosine kinase (RTK)-Ras-Raf-MEK-Erk cascade is frequently mutated in cancer, but it is not known whether Erk is a sole mediator of the pathway's oncogenicity, and what degree of Erk activity is required for oncogenicity. Also, it is assumed that high Erk activity is required to impose and maintain oncogenicity, but the exact degree of required activity is not clear. We report that induced expression of the intrinsically active variant Erk1^R84H in mouse liver gave rise to hepatocellular carcinoma (HCC). Intriguingly, the phosphorylated/active form of Erk1^R84H was dramatically downregulated during HCC development, and became almost undetectable in mature tumors. Similarly, in Erk1^R84H-transformed NIH3T3 cells, the phosphorylated/active form of Erk1^R84H was undetectable. Thus, 1) Erk1 could by itself cause HCC in mice, suggesting that it is the major or even the sole mediator of the cascade's oncogenicity. 2) Erk1^R84H-induced tumors (and other tumors) are maintained by a minimal Erk activity. 3) Erk1^R84H is probably the driver of the malignancy in patients that carry the R84H mutation.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-faceted discovery strategy identifies functional antibodies binding to cysteine-rich domain 1 of hDKK1 for cancer immunotherapy via Wnt non-canonical pathway.","authors":"Linya Wang, Sean M Peterson, Marisa Yang, Ana G Lujan Hernandez, Tom Z Yuan, Zhen Han, Vishwas Prabhu, Kara Y Chan, Cameron F Hu, Mouna Villalta, Tammy Htoy, Paul VanDyke, Carson Holliday, Hector Franco, Hansika Wadhwa, Hoa Giang, Ryan Stafford, Fumiko Axelrod, Aaron Sato","doi":"10.1038/s41388-025-03445-6","DOIUrl":"https://doi.org/10.1038/s41388-025-03445-6","url":null,"abstract":"<p><p>Wnt signaling is important in embryonic development and tumorigenesis. These biological effects can be exerted by the activation of the β-catenin-dependent canonical pathway or the β-catenin-independent non-canonical pathway. DKK1 is a potent inhibitor of Wnt signaling by competing with Wnt binding to LRP5/6 co-receptors. DKK1 is tumorigenic in multiple cancer types and immunosuppressive in NK cells. Emerging evidence indicates that DKK1 is involved in T cell differentiation and induces cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms by which DKK1 affects cancer and immune cells have received considerable attention. Using Twist's precision DNA writing technologies, we created phage display libraries with a diversity greater than 1 × 10¹⁰ individual members, and machine learning models were utilized for optimal discovery. We found that anti-DKK1 antibodies blocked the binding of DKK1 to LRP co-receptors. Binding of antibodies to different cysteine-rich domains (CRDs) of hDKK1 leads to different activation effects. In vitro functional assays showed that the interaction of Wnt with LRP5/6 co-receptors was restored in the presence of anti-DKK1 antibodies binding to DKK1 C-terminal CRD2, resulting in the upregulation of Wnt canonical TCF/LEF signaling and reactivation of osteoblast differentiation. Moreover, anti-DKK1 antibodies binding to DKK1 N-terminal CRD1 induced Wnt non-canonical JNK phosphorylation, immune cell activation, and tumor cell cytotoxicity. In vivo studies indicated that these anti-DKK1 antibody leads targeting DKK1 CDR1 are potent in inhibition of tumor growth and may have promising efficacy as cancer immunotherapy due to activation of the Wnt non-canonical pathway.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GD3 synthase drives resistance to p53-induced apoptosis in breast cancer by modulating mitochondrial function.","authors":"Vivek Anand, Fouad El-Dana, Natalia Baran, Jenny Borgman, Zheng Yin, Hong Zhao, Stephen T Wong, Michael Andreeff, V Lokesh Battula","doi":"10.1038/s41388-025-03432-x","DOIUrl":"https://doi.org/10.1038/s41388-025-03432-x","url":null,"abstract":"<p><p>TP53 mutations are common in breast cancer (BC) and are associated with poor prognosis. GD3 synthase (GD3S/ST8SIA1), a gene associated with breast cancer stem cells, is upregulated in tumors with p53 mutations. However, the functional relationship between GD3S and p53 is unknown. Here, we show that GD3S levels are highest in breast tumors with specific p53 mutations. Functional studies revealed that wild-type (WT) p53 inhibits GD3S expression, whereas mutation in p53 enhances GD3S expression by upregulating GD3S promoter activity. Moreover, we found that GD3S inhibits wild-type p53-induced apoptosis in BC cells, while BC cells harboring gain-of-function p53 mutations are dependent on GD3S for their growth. Mechanistic insights indicate that GD3S strengthens mitochondrial function by regulating their oxygen consumption rate and membrane polarity. Our findings demonstrate that specific GOF p53 mutations rely on GD3S to exert their tumor-promoting effects and that GD3S is a novel anti-apoptotic factor in BC cells. Stabilizing WT p53 and reducing mutant p53 levels downregulates GD3S expression, thereby augmenting apoptosis. GD3S overexpression counteracts the cell death triggered by WT p53 stabilization in BC cells, as well as that triggered by p53 knockdown in cells with specific GOF p53 mutations, which suggests that GD3S helps confer apoptosis resistance.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphorylation of USP32 by CDK5 regulates Rap1 stability and therapeutic resistance in pancreatic ductal adenocarcinoma.","authors":"Yanxia Jiang, Dexiang Ji, Wen Chen, Yuanzhe Zhu, Ming Luo, Rui Zou, Yilun Fu, Ping Huang, Qing Shi, Dejie Wang, Zhiwang Song","doi":"10.1038/s41388-024-03263-2","DOIUrl":"https://doi.org/10.1038/s41388-024-03263-2","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal human cancer. Gemcitabine-based chemotherapy remains the cornerstone for advanced PDAC. However, resistance to chemotherapy greatly limits its clinical therapeutic efficacy. Accordingly, the identification of novel therapeutic targets to overcome chemoresistance and improve prognosis is urgently needed. Screening of deubiquitinase family members, tandem affinity purification, mass spectrometry, and RNA sequencing (RNA-Seq) analysis were performed to predict the interactions and function of the CDK5-USP32-Rap1 axis in PDAC. In vitro and in vivo experiments were performed to elucidate the regulatory mechanism and biological roles of this axis in glycolytic reprogramming and chemoresistance in PDAC. Finally, TCGA database analysis and immunohistochemistry were performed to determine the expression and clinical significance of CDK5, USP32, and Rap1 in PDAC tissues. USP32 was identified as a bona fide deubiquitinase of Rap1. USP32 deubiquitinates and stabilizes Rap1, thereby promoting glycolytic reprogramming and chemoresistance in PDAC cells. Moreover, we unexpectedly found that CDK5-mediated phosphorylation of USP32 is required for its deubiquitinase activity toward Rap1 and drives malignant phenotypes of PDAC. Additionally, these functions can be significantly inhibited by pharmacological inhibition (roscovitine) or genetic ablation of CDK5. Importantly, combining a CDK5 inhibitor with gemcitabine has a synergetic anticancer effect. Indeed, the effectiveness of targeting CDK5 to sensitize PDAC cells to gemcitabine was confirmed in a patient-derived xenograft (PDX) model. CDK5 and USP32 expression is markedly elevated in PDAC samples and positively associated with Rap1 expression. Increased expression of CDK5, USP32, and Rap1 is significantly associated with poorer prognosis in PDAC. We identified the previously unrecognized oncogenic function and clinical importance of the CDK5-USP32-Rap1 axis, providing preclinical evidence for potential new combination strategies for PDAC therapy.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: CircVPRBP inhibits nodal metastasis of cervical cancer by impeding RACK1 O-GlcNAcylation and stability.","authors":"Chunyu Zhang, Hongye Jiang, Li Yuan, Yuandong Liao, Pan Liu, Qiqiao Du, Chaoyun Pan, Tianyu Liu, Jie Li, Yili Chen, Jiaming Huang, Yanchun Liang, Meng Xia, Manman Xu, Shuhang Qin, Qiaojian Zou, Yunyun Liu, Hua Huang, Yuwen Pan, Jiaying Li, Junxiu Liu, Wei Wang, Shuzhong Yao","doi":"10.1038/s41388-025-03440-x","DOIUrl":"https://doi.org/10.1038/s41388-025-03440-x","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: TP53 mutations upregulate RCP expression via Sp1/3 to drive lung cancer progression","authors":"Caihong Wang,&nbsp;Shaosen Zhang,&nbsp;Boyuan Ma,&nbsp;Yan Fu,&nbsp;Yongzhang Luo","doi":"10.1038/s41388-025-03441-w","DOIUrl":"10.1038/s41388-025-03441-w","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 22","pages":"1777-1779"},"PeriodicalIF":6.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-025-03441-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079353","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":"Derlin-3 manipulates the endoplasmic reticulum stress and IgG4 secretion of plasma cells in lung adenocarcinoma.","authors":"Lanlan Lin, Luyang Chen, Guofu Lin, Xiaohui Chen, Linlin Huang, Jiansheng Yang, Shaohua Chen, Ronghang Lin, Dongyong Yang, Fei He, Danwen Qian, Yiming Zeng, Yuan Xu","doi":"10.1038/s41388-025-03435-8","DOIUrl":"https://doi.org/10.1038/s41388-025-03435-8","url":null,"abstract":"<p><p>Derlin-3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, its potential biomechanisms in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains to be elucidated. In the present study, we found that Derlin-3 was predominantly elevated in LUAD tissues, and could predict worse prognosis of LUAD patients. ScRNA-seq analysis indicated that Derlin-3 was mainly enriched in B lymphocytes in the TME, especially in plasma cells. Moreover, Derlin-3 may be involved in ER stress and IgG4 secretion in plasma cells by targeting Hrd1/p38/PRDM1 pathway. While the aberrant IgG4 production may be an essential driver of the polarization of macrophages towards the M2 phenotype. Additionally, downregulation of Derlin-3 could inhibit plasma cells infiltration and M2 macrophage polarization in vivo. Our results indicated that Derlin-3 could shape TME via ER stress to harness immune function, which might serve as a promising immunotherapeutic target in LUAD.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}