Oncogenesis最新文献

{"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":"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":6.0,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13219483/pdf/","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":"OA","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":"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":6.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13213059/pdf/","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":"OA","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":"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":6.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13184315/pdf/","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":"OA","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":6.0,"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}

{"title":"Choroid plexus carcinoma: state of the field and emerging directions.","authors":"Ashley Thompson, Hannah Pescaru, Briana Griffin, Ryann M Fame","doi":"10.1038/s41389-026-00612-6","DOIUrl":"10.1038/s41389-026-00612-6","url":null,"abstract":"<p><p>Choroid plexus carcinoma (CPC) is a class of rare malignant life-threatening pediatric brain tumors, with a median survival of ~2.5-3 years [1, 2]. Recent advances in human genomics, cellular studies, and animal models have improved our understanding of the pathophysiology and molecular characteristics of CPC. However, because this cancer is rare, it remains understudied. This limited research has led to a limited understanding of the tumor's heterogeneity and molecular pathogenesis, resulting in fewer treatment options. Surgical resection remains the most significant contributor to patient survival and is often combined with chemotherapy, but tumors can still recur and metastasize. The post-surgical 5-year survival rate for CPC is only 60-65% and the adjuvant anti-mitotic radiation or chemotherapy included in standard treatment results in lifelong side effects for these children. Here we conduct a systematic review of existing literature and analyze the current body of research on CPC with special focus on preclinical models to highlight progress and barriers while emphasizing important open questions for improving patient treatment and longevity outcomes. This analysis underscores the importance of scholarly discussion and further exploration into the carcinogenesis of CPC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13172529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147628097","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":"GPX3 suppresses gallbladder cancer progression by modulating redox balance, glycolysis, and anti-tumor immunity.","authors":"Zuyi Ma, Jia Sun, Xin Wu, Changzhen Shang, Binglu Li","doi":"10.1038/s41389-026-00603-7","DOIUrl":"10.1038/s41389-026-00603-7","url":null,"abstract":"<p><p>Gallbladder cancer (GBC) is an aggressive malignancy characterized by metabolic plasticity and profound immune evasion. However, the functional role of glutathione peroxidase 3 (GPX3), a secreted antioxidant enzyme, in these processes remains unclear. Multi-omics analyses of paired GBC and adjacent non-tumor tissues revealed consistent downregulation of GPX3, which correlated with reactive oxygen species (ROS) accumulation and enhanced glycolytic activity. Functional restoration of GPX3 in GBC cells reduced intracellular ROS levels, suppressed the expression of glycolysis-related enzymes, and consequently impaired tumor proliferation, migration, and invasion. In xenograft models, GPX3 overexpression markedly attenuated tumor growth and lung metastasis. Notably, GPX3 restoration also enhanced CD8⁺ T cell infiltration and elevated pro-inflammatory cytokine production, suggesting reversal of tumor-associated immunosuppression. These findings identify GPX3 as a critical tumor suppressor that integrates redox regulation, metabolic reprogramming, and immune activation to restrict malignant progression. Targeting GPX3 or its downstream pathways may represent a promising therapeutic strategy to simultaneously suppress gallbladder cancer aggressiveness and reinforce anti-tumor immunity.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13172071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147609430","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":"Alternatively activated macrophages cause DNA damage through an arginase 1-mediated bystander effect and promote epithelial cell transformation.","authors":"Ram Babu Undi, Michael M Sutton, Evan Becker, Marie Gordon, Sara K Vesely, Samantha Ricketts, Rameswari Velayutham, William M Tierney, Courtney W Houchen, Naushad Ali, Mark M Huycke","doi":"10.1038/s41389-026-00611-7","DOIUrl":"10.1038/s41389-026-00611-7","url":null,"abstract":"<p><p>Colorectal oncogenesis involves progressive genetic and epigenetic alterations in colon epithelial cells. Classically activated M1 macrophages can generate bystander-induced mutations and neoplastic transformation in epithelial cells. Herein, we report a novel mechanism by which alternatively activated M2 macrophages also induce a bystander effect. Similar to M1 macrophages, M2-activated macrophages cause double-strand DNA breaks in targeted epithelial cells, activate multiple signaling pathways, induce a DNA repair response, and transform epithelial cells in vitro. The M2-induced bystander effect occurs through an arginase 1-mediated mechanism. This enzyme is secreted by M2 macrophages and increases extracellular L-ornithine that is imported by target cells. This leads to increased polyamine metabolism and intracellular hydrogen peroxide causing DNA damage. Arginase 1-positive M2-like macrophages were frequently detected in preneoplastic colon adenomas using multiplex immunofluorescence. A greater proportion of activated macrophages was noted in histologically normal colon than in adenomas or stage I colorectal cancer. In addition to M1-like and M2-like activated macrophages, many macrophages in the colon biopsies expressed a hybrid M1/M2 phenotype. Activated macrophages significantly correlated with double-strand DNA damage in colon epithelial cells and DNA damage repair response. These findings define a novel M2-induced bystander effect and support a role for activated macrophages in colorectal cancer initiation and progression.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13168261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147593838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The oncogenic control of nucleotide synthesis.","authors":"Olivia Vidal-Cruchez, Issam Ben-Sahra","doi":"10.1038/s41389-026-00608-2","DOIUrl":"10.1038/s41389-026-00608-2","url":null,"abstract":"<p><p>Proliferating cancer cells reprogramme metabolism to secure nucleotides and other macromolecules required for biomass accumulation and genome duplication. Beyond serving as DNA/RNA precursors, nucleotides act as energy currencies, second messengers, glycosyl donors, and modulators of cytoskeletal dynamics; sustaining adequate pools is therefore indispensable for tumour growth and progression. Oncogenic lesions, such as loss of TP53 or LKB1, hyperactive PI3K-AKT-mTORC1, and MYC or RAS, coordinate transcriptional programmes, substrate transport, and post-translational control of rate-limiting enzymes to elevate de novo purine and pyrimidine synthesis and shape salvage use. These circuits integrate glycolysis, the pentose-phosphate pathway, folate-dependent one-carbon metabolism, and glutamine/aspartate provisioning to channel carbon and nitrogen into ring assembly. In this review, we organize this landscape into an environment-shaped routing model that explains when tumours favour de novo versus salvage and how therapies reroute flux. We synthesise current mechanisms by which oncogenes and tumour suppressors regulate nucleotide synthesis in cancer and outline therapeutic implications, including inhibitors of pathway enzymes (e.g., DHODH, IMPDH), strategies that restrict precursor availability, and rational combinations with targeted agents or DNA-damaging therapies to exploit replication stress and metabolic vulnerabilities. Together, these insights highlight nucleotide metabolism as a central, drug-responsive nexus linking oncogenic signalling to malignant proliferation.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13043699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513866","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":"Correction: LXRα limits TGFβ-dependent hepatocellular carcinoma associated fibroblast differentiation.","authors":"Anita Morén, Claudia Bellomo, Yutaro Tsubakihara, Dimitris Kardassis, Wolfgang Mikulits, Carl-Henrik Heldin, Aristidis Moustakas","doi":"10.1038/s41389-026-00610-8","DOIUrl":"10.1038/s41389-026-00610-8","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13000235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147481367","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":"Teriflunomide modulates the PD-1/PD-L1 axis and enhances antitumor immunity in colorectal cancer.","authors":"Jung Ho Han, Eun-Ji Lee, Young-Hoon Park, Jung-Hye Ha, Kazi Rejvee Ahmed, Jang-Gi Choi, Hwan-Suck Chung","doi":"10.1038/s41389-026-00607-3","DOIUrl":"10.1038/s41389-026-00607-3","url":null,"abstract":"<p><p>Inhibitors that target the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint pathway have revolutionized cancer immunotherapy; however, many patients exhibit a limited response. In this study, we examined the potential of teriflunomide (TER), an FDA-approved drug for multiple sclerosis, as a novel immune checkpoint modulator for treating colorectal cancer (CRC). We determined the effect of TER on PD-L1 expression in human CRC cell lines, its direct binding to PD-1, and its impact on CD8⁺ T-cell function. Antitumor activity was determined in vivo using a humanized mouse model of hPD-1 knock-in mice implanted with hPD-L1 expressing MC38 tumor cells. TER treatment reduced PD-L1 expression in CRC cells and disrupted the PD-1/PD-L1 interaction directly. In vivo, TER significantly suppressed tumor growth without systemic toxicity, and enhanced the infiltration and activation of CD8⁺ T cells within tumors, as evidenced by increased granzyme B expression. Moreover, the antitumor efficacy of TER was abolished by the depletion of CD8⁺ T cells, which indicated its dependency on this cell population. These findings highlight TER as a promising immune checkpoint modulator that targets the PD-1/PD-L1 axis to promote CD8⁺ T-cell-mediated antitumor immunity. Because of its established safety profile, TER is a readily translatable therapeutic for enhancing cancer immunotherapy in CRC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13002968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147481286","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}