Oncogenesis最新文献

{"title":"Ubiquitin-specific protease 11 suppresses cuproptosis in colorectal cancer by regulating the ubiquitination and stability of ISCU.","authors":"Hailin Ke, Guowei Zhang, Weili Lin, Yuecui Jiang, Meina Wu, Yueyi Zhang, Weiyang Song, Fuhai Wang, Songling Yan","doi":"10.1038/s41389-026-00621-5","DOIUrl":"https://doi.org/10.1038/s41389-026-00621-5","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains one of the most common and deadly malignancies, with limited effective treatment options. Cuproptosis is a novel regulated cell death triggered by mitochondrial copper overload (Cu²⁺) and has been implicated in several cancers. However, the mechanisms governing cuproptosis in CRC are largely unknown. In this study, we investigated the role of ubiquitin-specific proteases (USPs), key regulators of protein stability, in modulating cuproptosis in CRC. Through integrative analysis of publicly available CRC transcriptomic datasets, we identified oncogenic USPs potentially involved in cuproptosis regulation. Among them, USP11 emerged as significantly overexpressed in CRC tissues, and its elevated expression was correlated with poorer patient survival. We next examined the functional role of USP11 in two CRC cell lines and patient-derived CRC organoids. Cells were treated with elesclomol and CuCl₂, a combination known to induce cuproptosis. Functional assays revealed that USP11 promotes cell viability, colony formation, survival, and migration/invasion and suppresses cuproptosis in response to treatment. Mechanistic studies showed that USP11 directly binds to and deubiquitinates ISCU, a scaffold protein essential for iron-sulfur cluster assembly and known to bind Cu²⁺. This deubiquitination stabilizes ISCU, thereby preventing its proteasomal degradation. Rescue experiments further confirmed that ISCU is a key downstream effector mediating USP11's cuproptosis resistance effect. Finally, in patient-derived CRC organoid models, knockdown of USP11 significantly enhanced cuproptosis upon elesclomol/CuCl₂ treatment, validating our in vitro findings. Collectively, our work identifies USP11 as a novel inhibitor of cuproptosis in CRC, acting through the stabilization of ISCU. This newly uncovered USP11-ISCU axis contributes to tumor resistance against cuproptotic stress and highlights a potential therapeutic target for sensitizing CRC to copper-induced cell death.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840356","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":"Metabolic modulation of immune cell function: mechanisms and therapeutic implications in cancer immunotherapy.","authors":"Nina Fenouille, Camille Lobry, Lina Benajiba, Alexandre Puissant","doi":"10.1038/s41389-026-00622-4","DOIUrl":"https://doi.org/10.1038/s41389-026-00622-4","url":null,"abstract":"<p><p>Immune cell function is remarkably plastic, allowing T cells, NK cells, and macrophages to transition from resting or quiescent states to proliferative, cytotoxic, or inflammatory programs. These functional shifts are tightly coupled to metabolic reprogramming, which not only fuels energy and biosynthesis but also shapes epigenetic and transcriptional landscapes that guide immune responses. In this review, we highlight how intrinsic metabolic pathways which include glycolysis, fatty acid oxidation, amino acid metabolism, and TCA cycle intermediates, regulate T and NK cell proliferation, cytotoxicity, memory formation, and epigenetic programs. We also examine macrophages, whose polarization into pro-inflammatory M1 or tissue-reparative M2 states is orchestrated by distinct metabolic programs such as arginine metabolism, oxidative phosphorylation, and fatty acid oxidation, with consequences for local immune regulation. We then explore how tumors exploit these metabolic dependencies to create hostile microenvironments that restrict nutrients, accumulate immunosuppressive metabolites, and dampen immune cell activity. Finally, we discuss emerging metabolic interventions designed to restore immune fitness, enhance the efficacy of immune checkpoint inhibitors, and improve the persistence and cytotoxicity of adoptive T cell therapies, including CAR-T cells, in nutrient-deprived and hypoxic tumor niches. By linking immune cell plasticity to metabolic control, this review provides a framework for understanding how metabolism shapes immunity and identifies strategies to harness these pathways for next-generation cancer immunotherapies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840435","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":"HPCAL1 promotes colorectal cancer progression via TCF7/p65-mediated Wnt ligand upregulation and Wnt/β-catenin pathway activation.","authors":"Linna Cheng, Huiyang Zhang, Liqun Guo, Qing Zhang, Yuanyuan Zhang, Qi Xie, Shuai Zhou, Dongpeng Wen, Wenchao Chen, Zhikai Wang, Jiancheng Zhang, Rick F Thorne, Zunmin Zhu","doi":"10.1038/s41389-026-00618-0","DOIUrl":"https://doi.org/10.1038/s41389-026-00618-0","url":null,"abstract":"<p><p>Abnormal Wnt/β-catenin pathway activation drives colorectal cancer (CRC) tumorigenesis, yet effective targeted therapies remain elusive. Given HPCAL1's established dual tumor-suppressive and oncogenic roles in other cancers, this study investigates its function in CRC to assess the therapeutic potential. Bioinformatic analyses of publicly available CRC datasets supported by in-house cohort studies linked high HPCAL1 expression in primary CRC tissues with clinicopathological factors associated with metastasis and worsened patient outcomes. Knockdown and overexpression studies in cell lines showed that HPCAL1 positively contributes to CRC cell motility and invasion, as well as proliferation in vitro and in vivo in xenografts. RNA sequencing linked HPCAL1 expression with the Wnt/β-catenin pathway, demonstrating positive correlations with Wnt ligands in CRC models and clinical samples. Biochemical approaches showed HPCAL1 augmented the activation and nuclear localization of β-catenin. Moreover, HPCAL1 formed distinct complexes with β-catenin in tandem with the TCF7 or p65 transcription factors, in turn, differentially transactivating Wnt6, Wnt7A, and Wnt11 ligands. Notably, the anticancer activity of desloratadine against CRC cells, a pharmacological inhibitor of HPCAL1, functioned by curtailing Wnt6, Wnt7A, and Wnt11 expression and suppressing Wnt/β-catenin signaling. Collectively, these findings indicate that HPCAL1 is a significant contributor to the clinical aggressiveness of CRC with oncogenic effects intrinsically linked with sustaining canonical Wnt pathway activation. Furthermore, drug targeting experiments provide proof-of-principle evidence for promoting HPCAL1 as a therapeutic target for countering activated Wnt/β-catenin signaling in colorectal cancer.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840268","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":"Inhibition of LIMK by Cofilin-1 peptidomimetics enhances actin depolymerization and reduces metastasis of non-small cell lung cancer.","authors":"Min-Ying Lin, Jyh-Der Leu, Chun-Yi Wu, Liang-Cheng Chen, Yi-Jang Lee","doi":"10.1038/s41389-026-00624-2","DOIUrl":"https://doi.org/10.1038/s41389-026-00624-2","url":null,"abstract":"<p><p>Metastasis is a major contributor to the mortality and morbidity of human non-small cell lung cancer (NSCLC), driven by actin cytoskeletal rearrangements that enhance cancer cell motility and invasiveness. Cofilin-1 (CFL-1), a key actin-binding protein regulated by LIM kinase (LIMK), controls actin turnover through phosphorylation at serine-3. However, the role of CFL-1 phosphorylation in lung cancer metastasis remains unclear. In this study, in silico analysis revealed that high LIMK/CFL-1 expression correlates with poor prognosis in lung cancer patients. Although total CFL-1 levels were elevated across NSCLC cell lines, its serine-3 phosphorylation showed a stronger association with cellular invasiveness. To therapeutically target this pathway, we developed a cofilin mimetic peptide (CMP) designed to competitively inhibit endogenous CFL-1 phosphorylation. CMP treatment selectively accumulated in LIMK-overexpressing lung cancer cells both in vitro and in vivo, and effectively suppressed actin stress fiber formation by enhancing actin depolymerization. Acting as a competitive decoy of LIMK, CMP reduced cancer cell motility and invasion, and significantly inhibited metastatic progression in orthotopic NSCLC mouse models. Importantly, CMP treatment prolonged survival without inducing systemic toxicity. These findings highlight CFL-1 phosphorylation as a critical driver of lung cancer metastasis and propose peptidomimetic inhibition of the LIMK/CFL-1 pathway as a promising therapeutic strategy for metastatic NSCLC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840250","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":"Reprogramming lipid metabolism in pediatric cancers.","authors":"Vinzent L Lindemann, Nazek Noureddine, Raphael J Morscher","doi":"10.1038/s41389-026-00617-1","DOIUrl":"https://doi.org/10.1038/s41389-026-00617-1","url":null,"abstract":"<p><p>Metabolic reprogramming is a defining feature of malignant transformation and cancer cell growth. Pediatric cancers arise from genetic disruptions hijacking developmental programs by aberrant transcriptional networks. This coordinated rewiring shapes lipid metabolism through activation of biosynthetic pathways, membrane remodeling, and metabolic flexibility. This review synthesizes recent advances in the understanding of lipid metabolism reprogramming across pediatric cancers, examining four key areas: (1) transcriptional drivers that activate fatty acid and cholesterol synthesis; (2) lipid catabolism sustaining ATP, acetyl-CoA and NADPH pools under metabolic stress; (3) ferroptosis evasion through desaturation pathways and membrane remodeling; and (4) tissue-specific metabolic adaptations enabling metastasis to the bone marrow and cerebrospinal fluid. Despite extensive preclinical evidence identifying targetable vulnerabilities - including dependencies on FASN, SCD, and HMGCR - clinical impact remains to be proven. We discuss challenges of introducing therapies targeting lipid metabolism to the clinic and argue that the future lies in a better understanding of lipid flux and patient-specific dependencies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818239","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":"Cyclin E modulates vulnerability to CDC7 kinase inhibition.","authors":"Adam P Dommer, Robert Kyne, Jianxin Wang, Thomas N O'Connor, Amnon Koren, Erik S Knudsen, Agnieszka K Witkiewicz","doi":"10.1038/s41389-026-00613-5","DOIUrl":"https://doi.org/10.1038/s41389-026-00613-5","url":null,"abstract":"<p><p>CCNE1 (cyclin E) is frequently amplified or overexpressed in triple-negative breast cancer (TNBC) as compared with luminal subtypes. Cyclin E is associated with chromosomal instability and poor outcome, and overexpression promotes replication stress (fork stalling) in S-phase through impaired MCM chromatin loading and deregulated replication origin firing. Thus, approaches leveraging cyclin E-induced replication stress could lead to the development of promising therapeutic strategies. Here, we studied the effects of cell division cycle 7 (CDC7) kinase inhibition in TNBC cells overexpressing cyclin E. Cyclin E overexpression enhanced sensitivity to CDC7 inhibition, reducing proliferation and colony-forming capacity. This was accompanied by delays in replication timing and cell accumulation with ≥4 N DNA content. Conversely, CCNE1 knockdown rescued proliferation and colony outgrowth in the presence of CDC7 inhibition and reversed accumulation with ≥ 4N DNA content. CRISPR screening revealed cyclin-dependent kinase 8 (CDK8) as conferring resistance to CDC7 inhibition in a CCNE1-amplified cell line. Combined CDC7 and CDK8 inhibition significantly reduced proliferation and colony-forming ability, led to ≥4 N DNA content, and reduced tumor volume and mass in vivo. Together, this work identifies the enhanced vulnerability of cyclin E-overexpressing TNBC cells to CDC7 kinase inhibition and substantial synergy when combined with CDK8 inhibition.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777482","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":"PRMT6-mediated EZH2 arginine methylation is critical for breast cancer development.","authors":"Xue Han, Maoxiang Zhang, Chao Lu, Hui Xu, Shiyu Du, Chenjing Yue, Zhenhai Yu","doi":"10.1038/s41389-026-00619-z","DOIUrl":"https://doi.org/10.1038/s41389-026-00619-z","url":null,"abstract":"<p><p>Enhancer of zeste homologue 2 (EZH2), as a key histone methyltransferase, is elevated in multiple malignant tumours, which leads to poor prognosis. However, the underlying mechanisms for mediation of EZH2 enzyme activity remain elusive. Here, we report that PRMT6 asymmetrically dimethylates EZH2 at R509 to promote the bindings between EZH2 and other core component of the polycomb repressive complex 2 (PRC2), which enhances PRC2 induced methylation of histone H3 at K27. EZH2 R509 methylation blocks the expression of PRC2 target genes, leading to breast tumorigenesis in vitro and in vivo. Combination of PRMT6 inhibitor EPZ020411, and EZH2 inhibitor GSK126 effectively suppresses breast tumour growth in the mouse xenografts. Furthermore, immunohistochemical analyses demonstrate there is a positive correlation between PRMT6 and meR509-EZH2 expression in the breast cancer tissues. Consistently, PRMT6 mediated EZH2 R509 methylation is also confirmed in PRMT6-knockout mice. Our findings reveal that PRMT6 inhibitors might be promising combination therapy for EZH2-targeting cancer.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717745","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":"Metastasis suppressing properties of the cell-surface anchored serine protease prostasin: new functional and mechanistic insights from breast cancer.","authors":"Joseph G Lundgren, Michael G Flynn, Ani R Winkler, Brianna N Rivera, Lauren M Tanabe, Paul M Stemmer, Li-Mei Chen, Karl X Chai, Karin List","doi":"10.1038/s41389-026-00615-3","DOIUrl":"https://doi.org/10.1038/s41389-026-00615-3","url":null,"abstract":"<p><p>Serine proteases play multifaceted roles in cancer, affecting tumor formation, progression, and metastasis. While most serine proteases studied act as tumor promoters by remodeling the extracellular matrix and activating signaling pathways, others can function as tumor suppressors. Prostasin is a glycosylphosphatidylinositol-anchored serine protease that is expressed in epithelial tissues, including the ductal epithelium of the breast. We found that prostasin protein expression is lost in high-grade, poorly differentiated, invasive ductal carcinoma in both mice and humans. To test whether prostasin impacts tumor progression and metastasis, prostasin-deficient mice were crossed into the oncogene-induced transgenic MMTV-PymT mammary tumor model. While prostasin deficiency did not affect primary tumor growth, it resulted in a significantly increased spontaneous dissemination of cancer cells to the lungs, suggesting a causal relationship between the loss of prostasin expression and progression to distant metastasis of breast cancer. At the cellular level, re-expression of prostasin in human breast cancer cells that have lost endogenous prostasin attenuated their invasive properties. Importantly, silencing prostasin expression in non-transformed human mammary epithelial cells (HMECs) resulted in the disruption of epithelial integrity and the loss of tight junctions (TJs), an early hallmark of cells acquiring an invasive phenotype. Discovery proteomics identified HMEC-expressed fibronectin (FN) as a regulatory target of prostasin and revealed increased levels of FN upon prostasin silencing. Mechanistically, cellular FN plays a causal role in TJ integrity in HMECs, and concomitant silencing of FN and prostasin rescues the defects caused by prostasin loss. Prostasin-mediated FN regulation represents a novel mechanism for regulating mammary epithelial cell TJ integrity and a potential candidate pathway for targeted therapy in breast cancer patients.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147717755","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":"SREBP2 regulates CCDC25 expression and promotes tumor metastasis in Triple-Negative Breast Cancer.","authors":"Xingxian Lv, Hao Wang, Beibei Liang, Liyun Yang, Zhuozhuo Han, Wei Xie, Xiuhong Lu, Hao Yang, Gang Huang, Jian Zhao","doi":"10.1038/s41389-026-00614-4","DOIUrl":"https://doi.org/10.1038/s41389-026-00614-4","url":null,"abstract":"<p><p>This study investigates how cholesterol metabolism promotes metastasis in triple-negative breast cancer (TNBC). By integrating public databases, we identified a positive correlation between the cholesterol metabolism transcription factor SREBP2 and the membrane receptor CCDC25 in TNBC, and their co-high expression was strongly associated with poor patient prognosis. Mechanistically, we found that SREBP2 directly binds to the promoter region of CCDC25 and activates its transcription, upregulating its expression. Functionally, the SREBP2-CCDC25 axis enhanced TNBC cells migration and invasion and promoted neutrophil extracellular traps (NETs) formation. In vivo, SREBP2 overexpression accelerated lung metastasis in TNBC, increased levels of NETs markers and elevated CCDC25 expression in metastatic lesions. Importantly, pharmacological inhibition of the SCAP-SREBP2 pathway with Fatostatin or Lycorine suppressed CCDC25 expression, reduced NETs formation, and attenuated metastasis. Collectively, these findings define a cholesterol-driven SCAP-SREBP2-CCDC25-NETs axis that promotes TNBC metastasis and highlight this pathway as a potential therapeutic target.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675433","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":"Correction: Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma.","authors":"Mal Irvine, Ashleigh Stewart, Bernadette Pedersen, Suzanah Boyd, Richard Kefford, Helen Rizos","doi":"10.1038/s41389-026-00616-2","DOIUrl":"10.1038/s41389-026-00616-2","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13069084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147654497","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}