Oncogenesis最新文献

{"title":"Correction: NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma.","authors":"Xiaoye Jin, Xiayuan Lou, Haoxiang Qi, Chao Zheng, Bo Li, Xuerong Siwu, Ren Liu, Qiaoli Lv, An Zhao, Jian Ruan, Ming Jiang","doi":"10.1038/s41389-026-00670-w","DOIUrl":"https://doi.org/10.1038/s41389-026-00670-w","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stanniocalcin 1 contributes to glioma stem cells phenotypic plasticity through NOTCH1/STAT3/GFPT2 axis.","authors":"Feng Tian, Kangming Zhu, Yanfei Sun, Shuhua Guo, Xing Guo, Chuanxin Wang, Shuo Xu","doi":"10.1038/s41389-026-00653-x","DOIUrl":"10.1038/s41389-026-00653-x","url":null,"abstract":"<p><p>Glioma stem cells (GSCs) are key drivers of glioblastoma (GBM) tumorigenesis, invasion, therapy resistance, and recurrence and exhibit remarkable phenotypic plasticity. Stanniocalcin 1 (STC1) has been implicated in tumor progression and cancer stemness; however, its role and the molecular mechanisms through which it shapes GSC plasticity and malignant traits remain poorly understood. Here, transcriptomic RNA sequencing identified STC1 as a malignancy-associated gene enriched in GBM and mesenchymal (MES)-like GSCs. Comprehensive bioinformatic analyses further validated that STC1 was highly expressed in MES-like GBM/GSCs and closely associated with poor patient survival. Functional studies revealed that STC1 promoted multiple malignant properties of GSCs, including self-renewal, migration, invasion, tumorigenicity, and cellular plasticity. Conversely, STC1 silencing attenuated these effects. Mechanistically, STC1 activated the NOTCH1/STAT3 signaling cascade, leading to transcriptional upregulation of GFPT2, a key rate-limiting enzyme of the hexosamine biosynthetic pathway. This subsequently enhanced global O-GlcNAcylation, including modification of P65, thereby facilitating GSC plasticity and malignant progression. Genetic and pharmacological interventions targeting this signaling axis effectively mitigated the oncogenic effects driven by STC1. In conclusion, our study reveals that STC1 is a key regulator of GSC phenotypic plasticity and aggressiveness through the NOTCH1/STAT3/GFPT2/O-GlcNAcylation pathway. These results provide new mechanistic insights into GBM progression and suggest that targeting STC1-associated signaling networks may represent a potential therapeutic strategy for GBM.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183363","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":"CYBRD1 is transcriptionally regulated by RUNX1 and mediates JAK2/STAT3 signaling activation during ovarian cancer progression.","authors":"Yalong Deng, Qiyu Gan, Xia Huang, Liang Zhu, Lina Liu, Guozeng Wang, Linlin Chang, Rui Shi, Sufeng Qiang, Wenzhi Duan, Qin Liu, HuiMin Lei, Jingxin Cheng","doi":"10.1038/s41389-026-00646-w","DOIUrl":"10.1038/s41389-026-00646-w","url":null,"abstract":"<p><p>Metastasis and chemoresistance are the leading causes of death in high-grade serous ovarian carcinoma (HGSOC). Our previous studies revealed that the membrane protein cytochrome b reductase 1 (CYBRD1) is a critical prognostic marker for HGSOC, but its role in HGSOC progression and molecular mechanisms remain unclear. Here, we reveal that CYBRD1 is a druggable factor that drives chemoresistance and tumor progression in HGSOC. Importantly, compared with that in their cisplatin-sensitive counterparts, CYBRD1 expression is elevated in cisplatin-resistant cells. Through genetic manipulation, we showed that CYBRD1 inhibition effectively re‑sensitizes cells to cisplatin and suppresses proliferation, migration, and invasion. Targeted gene expression profiling indicated that CYBRD1 inhibition markedly attenuated JAK2/STAT3 signaling. Using point mutants, we confirmed that phosphorylation of CYBRD1 at Tyr252 is essential for the interaction with JAK2, subsequent activation of JAK2/STAT3 signaling and mediating HGSOC progression. CYBRD1 inhibition significantly restored cisplatin sensitivity and exerted a synergistic tumoricidal effect. In vivo, combined CYBRD1 inhibition and cisplatin markedly reduced tumor metastasis. Furthermore, we found that RUNX1 regulates CYBRD1 transcription. These findings highlight that the combination of CYBRD1 inhibitors and conventional chemotherapy is a promising therapeutic strategy for HGSOC, especially in chemoresistant patients.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128227","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":"Apoptosis-driven chromosomal rearrangements in cancer: CAD cleavage, nuclear architecture, and microhomology-mediated end joining.","authors":"Sang-Nee Tan","doi":"10.1038/s41389-026-00645-x","DOIUrl":"10.1038/s41389-026-00645-x","url":null,"abstract":"<p><p>Chromosomal rearrangements are hallmarks of many cancers, yet the mechanisms governing breakpoint selection remain incompletely understood. Emerging evidence suggests that sublethal apoptotic signaling may contribute to structural genome remodeling. Oxidative stress and inflammatory stimuli trigger caspase activation and the release of caspase-activated DNase (CAD), which preferentially cleaves DNA at matrix association regions/scaffold attachment regions (MAR/SARs) that anchor chromatin loops to the nuclear scaffold. When apoptotic execution is incomplete and cells undergo recovery, a process termed anastasis, CAD-induced double-strand breaks (DSBs) can be repaired through error-prone end-joining pathways, including classical non-homologous end joining (cNHEJ) and microhomology-mediated end joining (MMEJ), producing rearrangements enriched at MAR/SAR-associated genomic regions. Drawing on mechanistic studies in leukemia and experimental evidence in nasopharyngeal carcinoma (NPC), this review outlines a framework linking apoptotic DNA fragmentation, nuclear architecture, and error-prone repair to recurrent structural variations, and discusses how shared inflammation- and virus-associated oxidative stress may promote analogous mechanisms of breakpoint formation in other malignancies. The convergence of findings across hematologic and epithelial malignancies strengthens the biological plausibility and potential generalizability of this model across inflammation- and stress-associated cancers. This perspective suggests that at least a subset of cancer-associated chromosomal rearrangements may arise not purely as stochastic by-products of genomic instability, but as structured outcomes of dysregulated cell-death programs acting on vulnerable chromatin domains. Beyond its mechanistic implications, this framework may inform biomarker discovery through apoptosis-associated breakpoint features and highlight potential therapeutic vulnerabilities in apoptosis-surviving cells, including dependence on polymerase theta-mediated repair or regulation of apoptotic execution.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13408182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148605941","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":"Lung adenocarcinoma cell-derived lactate activates CAFs to promote macrophage M2 polarization via exosomal miR-214-5p.","authors":"Leilei Tao, Fengbiao Guo, Xiaobei Liu, Xiao Zhao, Ya Xue, Weigang Bian, Jing Chen, Shaoyi Zhang, Bin Li","doi":"10.1038/s41389-026-00641-1","DOIUrl":"10.1038/s41389-026-00641-1","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that can drive cancer progression and immune evasion. Here, we identify a novel pathway in which lactate produced by lung adenocarcinoma (LUAD) cells activates normal fibroblasts into CAFs, inducing high expression of microRNA miR-214-5p. The CAFs secrete miR-214-5p via exosomes, which in turn polarizes tumor-associated macrophages (TAMs) toward the immunosuppressive M2 phenotype. Mechanistically, exosomal miR-214-5p targets the transcriptional repressor BHLHE41 in macrophages, relieving its inhibition on M2-polarization genes. We further demonstrate that lactate accumulation epigenetically upregulates miR-214-5p in CAFs by increasing histone H3 lysine 9 lactylation (H3K9la) at the DNM3OS/miR-214 gene locus, independently of the lactate receptor GPR81. Lactate also enhances the loading of miR-214-5p into exosomes by inducing lactylation of the RNA-binding protein YBX1, which binds miR-214-5p and facilitates its exosomal export. In a mouse co-implantation model of LUAD, pharmacological blockade of tumor lactate production (LDH inhibition) reduced CAF activation, TAM M2 polarization, miR-214-5p levels, and tumor growth. Our findings uncover a lactate-driven CAF-TAM signaling axis via exosomal miR-214-5p, highlighting potential therapeutic targets to counteract tumor immune evasion in lung adenocarcinoma.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422948","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":"Combined therapy with ALK inhibitors and a novel EGFR-targeting antibody‒drug conjugate as a strategy for ALK-rearranged non-small cell lung cancers.","authors":"Lanwen Zhang, Xiaofan Wu, Jingfei Gao, Dandan Zhou, Jing Xin, Shiyu Zhu, Zhuorong Li, A-Long Cui, Qingfang Miao, Ruijuan Gao","doi":"10.1038/s41389-026-00644-y","DOIUrl":"10.1038/s41389-026-00644-y","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death. Targeted monotherapies against the actionable oncogenic drivers, including anaplastic lymphoma kinase (ALK) rearrangement and epidermal growth factor receptor (EGFR) dysregulation, are well-established for molecularly selected NSCLC patients. However, therapeutic resistance remains a major clinical challenge, and combinatorial strategies targeting distinct signaling pathways may overcome the limitations of single-agent targeted therapies. LR004-VC-MMAE, a novel EGFR-targeting antibody‒drug conjugate (ADC), shows potent antitumor efficacy in multiple EGFR-positive xenografts, yet its therapeutic potential in ALK-rearranged NSCLC remains largely unexplored. Here, we evaluated a novel combinatorial strategy using ALK inhibitors (crizotinib, ceritinib, alectinib, and lorlatinib) in combination with LR004-VC-MMAE in ALK-rearranged NSCLC models. We found that both ALK and cell-surface EGFR were highly expressed in ALK-rearranged NCI-H3122 and NCI-H2228 cell lines but were expressed at low levels in the ALK-wild-type NCI-H460 cell line. All ALK inhibitor-ADC regimens synergistically suppressed proliferation in ALK-rearranged NSCLC cells, while exerting little synergy in ALK wild-type and EGFR-low counterparts. Moreover, crizotinib or ceritinib combined with LR004-VC-MMAE induced significantly greater apoptosis in NCI-H3122 cells compared with either single agent. Mechanistically, the crizotinib-LR004-VC-MMAE combination markedly downregulated ALK and EGFR expression and triggered apoptosis via mitochondrial depolarization-mediated caspase cascade activation and endoplasmic reticulum stress-induced unfolded protein response. In NCI-H3122 xenografts, this combination achieved synergistic tumor inhibition without increased toxicity compared with either treatment alone. Collectively, our findings demonstrate the synergistic antitumor activity of ALK inhibitor plus LR004-VC-MMAE against ALK-rearranged, EGFR-high NSCLC, providing a mechanistic rationale for further clinical development of this combination strategy.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422975","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":"Obesity-driven extracellular vesicle signaling in cancer: mechanistic insights and clinical implications.","authors":"Lakshmi Narasimhan Chakrapani, Jessica Velasquez, Joshika Suresh, Subasri Durga Sridhar, Ramya Sankaran, Suriya Prakash Arivazhagan, Archana Shanmugam, Kalpana Deepa Priya Dorayappan, David M O'Malley, Thangavel Muthusamy, Karuppaiyah Selvendiran","doi":"10.1038/s41389-026-00640-2","DOIUrl":"10.1038/s41389-026-00640-2","url":null,"abstract":"<p><p>Obesity is a rapidly escalating global health challenge and a major, modifiable driver of cancer risk and poor outcomes across at least 13 malignancies, including endometrial, colorectal, breast, pancreatic, hepatic, renal, ovarian, and esophageal adenocarcinoma. Beyond endocrine and metabolic effects, obesity establishes a tumor-permissive systemic state characterized by adipose hypoxia, chronic inflammation, insulin resistance, and adipokine imbalance. Here, we synthesize evidence that extracellular vesicles (EVs) serve as a central mechanistic conduit through which these obesity-associated stress programs are transmitted to tumor and stromal compartments, driving cancer initiation, progression, immune evasion, metastasis, and therapy resistance. Obesity amplifies EV biogenesis and reprograms EV cargo through hypoxia- and inflammation-responsive signaling and altered endosomal trafficking, enriching EVs with coordinated lipid, RNA, and protein modules that durably rewire recipient cells. Functionally, obesity-conditioned EVs reinforce oncogenic growth and survival signaling, promote epithelial plasticity and angiogenesis, remodel the tumor microenvironment toward immune suppression and extracellular matrix reorganization, and facilitate pre-metastatic niche formation. Clinically, EVs provide a stable, information-rich substrate for liquid biopsy development, with emerging EV signatures showing promise for early detection, risk stratification, and longitudinal disease monitoring in obesity-associated cancers. We conclude by outlining key mechanistic, technological, and translational priorities required to advance EV-based biomarkers and to therapeutically disrupt obesity-driven intercellular communication.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369115","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":"Integrated scRNA-Seq and functional profiling reveal CD52 as a driver of pancreatic ductal adenocarcinoma metastasis and immunosuppression.","authors":"Zeyu Zhang, Jinxin Tao, Yifan Fu, Yi Dong, Yuanyang Wang, Menggang Zhang, Liyuan Ye, Jiangdong Qiu, Yueze Liu, Hao Chen, Jianchun Xiao, Hua Huang, Zhe Cao, Gang Yang, Taiping Zhang","doi":"10.1038/s41389-026-00637-x","DOIUrl":"10.1038/s41389-026-00637-x","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy driven by rapid metastasis and a profoundly immunosuppressive microenvironment. While the surface glycoprotein CD52 is a known immunoregulator, its precise role in solid tumors remains controversial, partly due to its broad expression across diverse cell populations and its compartment-specific functions within the tumor microenvironment. In this study, we utilized integrated single-cell RNA sequencing (scRNA-seq), functional assays, and compartment-specific clinical validation to elucidate the tumor-intrinsic functions of CD52 in PDAC. We identified a highly plastic, restricted subpopulation of CD52-high malignant epithelial cells that actively drives metastasis initiation by enhancing cellular invasive capacity. Concurrently, we demonstrated that tumor-derived CD52 orchestrated a multi-layered immunosuppressive network that attenuates CD8 + T cell cytotoxicity, facilitating early immune evasion. Furthermore, by systematically separating expression sources, our clinical validation established that tumor-derived CD52 is a prognostic indicator of poor patient survival. These findings characterize CD52 as a critical, tumor-intrinsic driver of PDAC progression, highlighting its value as a prognostic biomarker and a therapy target in combination with immune checkpoint blockade to overcome innate therapeutic resistance in PDAC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339672","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":"Metabolic plasticity and therapeutic opportunity in cancer.","authors":"Shensi Shen","doi":"10.1038/s41389-026-00642-0","DOIUrl":"10.1038/s41389-026-00642-0","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13294493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148318316","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":"Editorial Expression of Concern: Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo.","authors":"A G Manente, D Valenti, G Pinton, P V Jithesh, A Daga, L Rossi, S G Gray, K J O'Byrne, D A Fennell, R A Vacca, S Nilsson, L Mutti, L Moro","doi":"10.1038/s41389-026-00639-9","DOIUrl":"10.1038/s41389-026-00639-9","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13279950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278141","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}