IF 9.1 1区医学

Oncogene Pub Date : 2026-10-19 DOI: 10.1038/s41388-026-04019-w

Hiroyuki Arai, Andrew Elliott, Yan Yang, Alex Farrell, Joshua Millstein, Fang-Shu Ou, Federico Innocenti, Jingyuan Wang, Francesca Battaglin, Priya Jayachandran, Sandra Algaze, Shivani Soni, Wu Zhang, Richard M Goldberg, Michael J Hall, Aaron James Scott, Jimmy J Hwang, Emil Lou, Benjamin A Weinberg, John Marshall, Sanjay Goel, Joanne Xiu, W Michael Korn, Alan P Venook, Heinz-Josef Lenz

{"title":"Activation of the endocytosis pathway stratifies subtypes and therapeutic sensitivity in colorectal cancer.","authors":"Hiroyuki Arai, Andrew Elliott, Yan Yang, Alex Farrell, Joshua Millstein, Fang-Shu Ou, Federico Innocenti, Jingyuan Wang, Francesca Battaglin, Priya Jayachandran, Sandra Algaze, Shivani Soni, Wu Zhang, Richard M Goldberg, Michael J Hall, Aaron James Scott, Jimmy J Hwang, Emil Lou, Benjamin A Weinberg, John Marshall, Sanjay Goel, Joanne Xiu, W Michael Korn, Alan P Venook, Heinz-Josef Lenz","doi":"10.1038/s41388-026-04019-w","DOIUrl":"https://doi.org/10.1038/s41388-026-04019-w","url":null,"abstract":"Endocytosis regulates receptor trafficking and signaling, yet its role in colorectal cancer (CRC) remains unclear. We analyzed transcriptomic data from 15,025 CRC tumors to evaluate gene expression in clathrin-mediated endocytosis (CME) and the endosomal sorting complexes required for transport (ESCRT) pathway. Pathway-level signatures were compared across consensus molecular subtypes (CMS) and examined in relation to oncogenic signaling programs, while individual endocytosis-related genes were evaluated for associations with clinical outcomes in an independent randomized trial cohort. Expression of CME and ESCRT pathways varied by CMS, with the highest expression in CMS4 and the lowest in CMS3. Endocytosis signatures correlated with multiple oncogenic signaling pathways, including MAPK, TGF-β, WNT, PI3K, NOTCH, and angiogenesis, suggesting broad links between endocytic activity and tumor biology. In the randomized phase III CALGB/SWOG 80405 trial, low expression of AP2M1-a core adaptor in the CME complex-was significantly associated with longer overall survival and progression-free survival in patients treated with anti-EGFR agents, but not in those receiving anti-VEGF agents. These findings suggest that endocytic trafficking may be associated with oncogenic signaling and differential therapeutic benefit in patients with metastatic CRC. The endocytosis pathway reflects biologically relevant heterogeneity in CRC and may help guide therapeutic stratification.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224656","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}

引用次数: 0

Phosphorylation of IRS4 at YY111/112 promotes LUSC progression via PI3K/AKT pathway activation. IRS4在YY111/112位点的磷酸化通过PI3K/AKT通路激活促进LUSC进展。

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-17 DOI: 10.1038/s41388-026-04015-0

Yilixiati Aihemaiti, Qiuhan Ren, Xiangling Jiang, Kaideya Wushaying, Ran Chen, Yanli Wang, Xian Zhao, Lei Xu, Zhi Yang, Jianxiu Yu, Jian Huang

{"title":"Phosphorylation of IRS4 at YY111/112 promotes LUSC progression via PI3K/AKT pathway activation.","authors":"Yilixiati Aihemaiti, Qiuhan Ren, Xiangling Jiang, Kaideya Wushaying, Ran Chen, Yanli Wang, Xian Zhao, Lei Xu, Zhi Yang, Jianxiu Yu, Jian Huang","doi":"10.1038/s41388-026-04015-0","DOIUrl":"https://doi.org/10.1038/s41388-026-04015-0","url":null,"abstract":"Lung squamous cell carcinoma (LUSC) lacks effective targeted therapies despite frequent hyperactivation of the PI3K/AKT pathway, and the contribution of adaptor proteins to this process remains poorly defined. Here, we identify Insulin Receptor Substrate 4 (IRS4) as a common substrate of Src kinase and the phosphatase RPTPα, and uncover a previously unrecognized, conserved phosphorylation site at YY111/112 within the IRS4 PH domain. Src-mediated phosphorylation at this site is essential for IRS4-driven proliferation, anchorage-independent growth, and invasiveness in LUSC cells. Mechanistically, phosphorylation at YY111/112 induces conformational rearrangements in IRS4 that enhance the recruitment of the p85β SH2 domain to the YXXM motif of IRS4, thereby promoting AKT activation without altering IRS4 protein stability or subcellular distribution. An IRS4-derived cell-permeable phosphopeptide containing pYY111/112 disrupts the Src-IRS4 interaction and significantly suppresses tumor growth in vivo in a YY111/112-dependent manner. Consistently, YY111/112 phosphorylation is markedly elevated in human LUSC tissues and correlates with advanced disease stages. Collectively, these findings define a Src-IRS4-PI3K/AKT signaling axis and identify YY111/112 as a critical regulatory site of IRS4 and a potential therapeutic vulnerability in LUSC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216408","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}

引用次数: 0

Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy. 肝脏特异性氨基酸代谢对肿瘤免疫治疗疗效的影响。

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-17 DOI: 10.1038/s41388-026-04023-0

Yuma Fukumoto, Fumiaki Mukohara, Momoko Iwatsuru, Youki Ueda, Hiroaki Kanzaki, Sadahisa Ogasawara, Jason Lin, Masahito Kawazu, Toshifumi Ninomiya, Naoya Kemmotsu, Joji Nagasaki, Shinichi Toyooka, Tsuyoshi Osawa, Takamasa Ishino, Yosuke Togashi

{"title":"Liver-specific amino acid metabolism impacts on efficacy of cancer immunotherapy.","authors":"Yuma Fukumoto, Fumiaki Mukohara, Momoko Iwatsuru, Youki Ueda, Hiroaki Kanzaki, Sadahisa Ogasawara, Jason Lin, Masahito Kawazu, Toshifumi Ninomiya, Naoya Kemmotsu, Joji Nagasaki, Shinichi Toyooka, Tsuyoshi Osawa, Takamasa Ishino, Yosuke Togashi","doi":"10.1038/s41388-026-04023-0","DOIUrl":"https://doi.org/10.1038/s41388-026-04023-0","url":null,"abstract":"The combination immunotherapies, including those with atezolizumab and bevacizumab (Atez/Bev), have become standard therapy for hepatocellular carcinoma (HCC). However, its efficacy remains limited and reliable biomarkers are lacking. In this study, we analyzed paired tumor and background liver tissues from Atez/Bev-treated HCC patients and found that high programmed cell death-1 (PD-1) expression in CD8+ tumor-infiltrating lymphocytes (TILs) correlated with therapeutic response independent of etiology. RNA sequencing on the tumor samples revealed that the branched-chain amino acid (BCAA)-related metabolic pathway was enriched in the group with high PD-1 expression in CD8⁺ TILs. Along with in vitro experiments, we identified the importance of BCAAs for activation and differentiation of CD8+ T cells. In addition, BCAA metabolism was related to response to PD-1 blockade in not subcutaneous but intrahepatic mouse model-specific manner. Actually, public dataset analyses revealed that high expression of BCAT1, a key enzyme in BCAA metabolism, was associated with poor prognosis in HCC, but not in other cancer types. These findings suggest the importance of liver-specific BCAA metabolism in antitumor immunity and highlight the need to assess the tumor microenvironment within its organ-specific metabolic context.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216363","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}

引用次数: 0

Dual novel compounds destroy mitochondrial morphology and function to treat glioblastoma by promoting the p62-mediated protein degradation of mitochondrial respiratory chain complex. 双重新化合物破坏线粒体形态和功能，通过促进p62介导的线粒体呼吸链复合物的蛋白质降解来治疗胶质母细胞瘤。

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-16 DOI: 10.1038/s41388-026-04018-x

Hanyi Xu, Yanping Huang, Dongyuan Su, Biao Hong, Qi Zhan, Qixue Wang, Longtao Cui, Chunchao Cheng, Yaqing Ding, Chunsheng Kang, Xiaoteng Cui

{"title":"Dual novel compounds destroy mitochondrial morphology and function to treat glioblastoma by promoting the p62-mediated protein degradation of mitochondrial respiratory chain complex.","authors":"Hanyi Xu, Yanping Huang, Dongyuan Su, Biao Hong, Qi Zhan, Qixue Wang, Longtao Cui, Chunchao Cheng, Yaqing Ding, Chunsheng Kang, Xiaoteng Cui","doi":"10.1038/s41388-026-04018-x","DOIUrl":"https://doi.org/10.1038/s41388-026-04018-x","url":null,"abstract":"Therapeutic efficacy of temozolomide (TMZ) remains limited, and GBM patients generally experience poor outcomes due to the presence of multiple mechanisms of TMZ resistance. Previously, we developed two novel compounds: EPIC-1027, which targets HOTAIR/PRC2 complex, and EPIC-1042, which disrupts interaction between PTRF and CAV1. In this study, we aim to establish a novel combinatorial strategy for GBM by targeting mitochondrial function. Proteomics was employed to evaluate global protein alterations induced by EPIC-1027 and EPIC-1042. Super-resolution microscopy and transmission electron microscopy were used to characterize changes in mitochondrial morphology. Metabolic flux analysis was performed to assess alterations in cellular energy metabolism following combined treatment. An intracranial GBM model was established to validate the anti-GBM efficacy of EPIC-1027 and EPIC-1042 in vivo. Combined treatment with EPIC-1027 and EPIC-1042 reduced the abundance of respiratory chain complex proteins by promoting p62-dependent protein degradation, resulting in severe mitochondrial damage. Both glycolytic activity and oxidative phosphorylation were markedly suppressed following EPIC-1027 and EPIC-1042 treatment. In vitro, EPIC-1027 and EPIC-1042 exerted a synergistic inhibitory effect on GBM cell proliferation and significantly induced apoptosis in an MGMT-independent manner. In vivo, combined treatment with EPIC-1027 and EPIC-1042 significantly attenuated tumor growth and prolonged survival in mice bearing orthotopic GBM. Our study demonstrates that combined treatment with EPIC-1027 and EPIC-1042 induces mitochondrial structural abnormalities and functional impairment, leading to suppressed proliferation and enhanced apoptosis. These findings identified a novel combinatorial therapeutic strategy targeting mitochondria for the treatment of glioblastoma.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207466","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}

引用次数: 0

Dynamic remodeling of the KRAS interactome by direct RAS inhibitors with distinct mechanism of action reveals convergent responses. 具有不同作用机制的直接RAS抑制剂对KRAS相互作用组的动态重塑显示出趋同反应。

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-16 DOI: 10.1038/s41388-026-04017-y

Yang Yang, Tingyu Liu, Charles Y Cho, Xianzhong Liu, Ansgar Brock, Doug Quackenbush, Kaisheng Chen, Frederick Lo, Cyril H Benes, Jacob R Haling

{"title":"Dynamic remodeling of the KRAS interactome by direct RAS inhibitors with distinct mechanism of action reveals convergent responses.","authors":"Yang Yang, Tingyu Liu, Charles Y Cho, Xianzhong Liu, Ansgar Brock, Doug Quackenbush, Kaisheng Chen, Frederick Lo, Cyril H Benes, Jacob R Haling","doi":"10.1038/s41388-026-04017-y","DOIUrl":"https://doi.org/10.1038/s41388-026-04017-y","url":null,"abstract":"KRAS is mutated in 30% of all human cancers. Small molecule inhibitors targeting KRAS with distinct mechanisms-of-action and variable specificities have entered the clinic, but their full effect on the RAS signaling network remains unclear. Here, we described the impact of RAS inhibition on the KRAS interactome using Proximity-dependent Biotin Identification. Two inhibitors were used: panRAS-ON, which forms a ternary complex between cyclophilin and RAS in the GTP-bound state; panKRAS-off, which binds to the KRAS switch II pocket. RAS inhibitors were found to significantly alter 16.5% of proteins in proximity to KRAS. Despite their distinct modality, the KRAS inhibitors induced highly correlated changes in the KRAS interactomes. Among KRAS-proximal proteins, Afadin was highly affected by RAS inhibition. AFDN is a key regulator of cell motility, invasion, and metastasis. Analysis of AFDN phosphorylation revealed that AKT only partially modulates p-Ser1718, while KRAS inhibition sufficiently abolished EGF-mediated AFDN phosphorylation. Silencing AFDN in a KRAS-driven non-small cell lung cancer model abolished chemotaxis and disrupted directional migration in an EGF-driven wound healing model. We demonstrated that KRAS is a central node in regulating growth factor-induced cell migration, and that KRAS inhibition plays a broader role than MAPK-mediated cell proliferation and survival.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195860","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}

引用次数: 0

Methylation-driven SOX18 nuclear translocation by IGF2BP1-stabilized METTL21A promotes lymphatic metastasis in gastric cancer. igf2bp1稳定的METTL21A甲基化驱动的SOX18核易位促进胃癌的淋巴转移。

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-15 DOI: 10.1038/s41388-026-04013-2

Ruofan He, Yi Zhang, Songyi Liu, Xiang Lin, Penghang Lin, Xiaoyu Pan, Yan Lin, Guangwei Zhu, Jianxin Ye, Xu Lin, Kunqi Chen

{"title":"Methylation-driven SOX18 nuclear translocation by IGF2BP1-stabilized METTL21A promotes lymphatic metastasis in gastric cancer.","authors":"Ruofan He, Yi Zhang, Songyi Liu, Xiang Lin, Penghang Lin, Xiaoyu Pan, Yan Lin, Guangwei Zhu, Jianxin Ye, Xu Lin, Kunqi Chen","doi":"10.1038/s41388-026-04013-2","DOIUrl":"https://doi.org/10.1038/s41388-026-04013-2","url":null,"abstract":"Gastric cancer (GC) is frequently associated with lymph node metastasis, which contributes to a poor prognosis; however, the underlying molecular mechanisms remain incompletely understood. In this study, we identify the N6-methyladenosine (m⁶A) reader IGF2BP1 as a critical driver of lymphatic metastasis in GC. IGF2BP1 is significantly upregulated in GC tissues with lymph node metastasis and is correlated with adverse clinical outcomes. Mechanistically, IGF2BP1 binds to the m⁶A-modified 3' untranslated region (3'UTR) of METTL21A mRNA, thereby enhancing its mRNA stability and expression levels. METTL21A, a non-histone lysine methyltransferase, interacts with and methylates the transcription factor SOX18, facilitating its nuclear translocation without altering protein stability. Once in the nucleus, SOX18 directly activates the transcription of CXCL12. Secreted CXCL12 promotes lymphangiogenesis and facilitates lymphatic metastasis through CXCR4 signaling. Functionally, both IGF2BP1 and METTL21A enhance tube formation and migration of lymphatic endothelial cells and promote lymphatic metastasis in GC. Notably, METTL21A knockout abolishes IGF2BP1-induced lymphangiogenesis, whereas SOX18 depletion eliminates the pro-lymphangiogenic effects of IGF2BP1. Our findings reveal a previously unrecognized signaling axis-IGF2BP1-METTL21A-SOX18-CXCL12-that links m⁶A-dependent post-transcriptional regulation with methylation-dependent transcriptional activation, offering potential therapeutic targets for the prevention of lymphatic metastasis in gastric cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195882","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}

引用次数: 0

TNFα-driven epigenetic upregulation of TIGIT creates a targetable vulnerability in tumors. tnf α驱动的表观遗传上调TIGIT在肿瘤中产生可靶向的易感性。

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-12 DOI: 10.1038/s41388-026-04008-z

Xuefeng Huang, Chaoyang Xiong, Minghang Yu, Jiyin Wang, Pu Liang, Guohong Li, Xi Wang

{"title":"TNFα-driven epigenetic upregulation of TIGIT creates a targetable vulnerability in tumors.","authors":"Xuefeng Huang, Chaoyang Xiong, Minghang Yu, Jiyin Wang, Pu Liang, Guohong Li, Xi Wang","doi":"10.1038/s41388-026-04008-z","DOIUrl":"https://doi.org/10.1038/s41388-026-04008-z","url":null,"abstract":"T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a key inhibitory receptor on cytotoxic lymphocytes, yet the mechanisms governing its context-dependent upregulation in tumors remain poorly defined. Here, we identify tumor necrosis factor-α (TNFα) signaling as an upstream driver of TIGIT expression. Integrated analyses of patient transcriptomic datasets revealed a consistent positive association between TNFα pathway activity and TIGIT expression across multiple cancer types, with strong concordance in melanoma and prognostic relevance in kidney renal clear cell carcinoma. Mechanistically, TNFα directly induced TIGIT expression in natural killer cells via TNFR2 signaling, increasing chromatin accessibility at distal TIGIT enhancers and promoting NF-κB and AP-1 recruitment together with BRD4 and P300. Functionally, combined anti-TNFα and anti-TIGIT treatment suppressed tumor growth and prolonged survival more effectively than either monotherapy in murine melanoma and colon cancer models. These findings define a TNFα-TNFR2-enhancer axis controlling TIGIT expression and provide a mechanistic rationale for dual TNFα and TIGIT targeting in inflamed tumors.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165079","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}

引用次数: 0

Correction: Targeting surface nucleolin induces autophagy-dependent cell death in pancreatic cancer via AMPK activation. 更正：靶向表面核蛋白通过AMPK激活诱导胰腺癌自噬依赖性细胞死亡。

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-12 DOI: 10.1038/s41388-026-04005-2

Cheng Xu, Yunfei Wang, Qiu Tu, Zhiye Zhang, Mengrou Chen, James Mwangi, Yaxiong Li, Yang Jin, Xudong Zhao, Ren Lai

引用次数: 0

PTK7 scaffolds DNA-PKcs to promote DNA damage response and immune evasion in triple-negative breast cancer. PTK7支架DNA- pkcs促进三阴性乳腺癌DNA损伤反应和免疫逃避

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-10 DOI: 10.1038/s41388-026-04011-4

Xueying Liu, Kejing Zhang, Yu Zhang, Yuejun Wang, Yuanjie Jiang, Qiao Duan, Liyan Fei, Juan Wei, Sheyu Zhang, Zhonglan Wang, Gaoyang Wang, Jianmin Wu, Yuzhi Luo, Yong Wei, Feng Ge, Lu Guo, Qin Wu

{"title":"PTK7 scaffolds DNA-PKcs to promote DNA damage response and immune evasion in triple-negative breast cancer.","authors":"Xueying Liu, Kejing Zhang, Yu Zhang, Yuejun Wang, Yuanjie Jiang, Qiao Duan, Liyan Fei, Juan Wei, Sheyu Zhang, Zhonglan Wang, Gaoyang Wang, Jianmin Wu, Yuzhi Luo, Yong Wei, Feng Ge, Lu Guo, Qin Wu","doi":"10.1038/s41388-026-04011-4","DOIUrl":"https://doi.org/10.1038/s41388-026-04011-4","url":null,"abstract":"Membrane proteins with nuclear localization often exert non-canonical functions. PTK7, an evolutionarily conserved pseudokinase and a prominent therapeutic target, is primarily recognized for its cell-surface signaling; however, its intracellular role in tumor biology remains unclear. Here, we identify a previously unrecognized role of PTK7 in coordinating DNA damage response and tumor immune response in triple-negative breast cancer (TNBC). Mechanistically, PTK7 translocates to the nucleus where it associates with DNA-dependent protein kinase (DNA-PKcs), acting as a molecular scaffold to enhance its kinase activation and facilitate non-homologous end-joining (NHEJ) repair. Loss of PTK7 impaired DNA-PKcs-associated non-homologous end-joining (NHEJ) repair, increased double-strand breaks, and subsequent activation of the STING-IFN axis. Furthermore, PTK7 deficiency significantly sensitizes TNBC tumors to anti-PD-1 therapy in vivo. Clinically, high PTK7 expression correlates with suppressed immune signatures and poor immunotherapy response in TNBC patients. Together, our findings uncover a PTK7-associated DNA repair and immune-evasion program in TNBC and nominate PTK7 as a potential biomarker and therapeutic target for improving immunotherapy response.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170167","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}

引用次数: 0

Adrenomedullin 2 drives intratumoral cancer cell invasion, intravasation and metastasis. 肾上腺髓质素2驱动肿瘤内癌细胞侵袭、内渗和转移。

IF 9.1 1区医学

Oncogene Pub Date : 2026-10-10 DOI: 10.1038/s41388-026-04012-3

Konstantin Stoletov, Seyedeh Sara Karimian, Douglas Brown, Alice Amitrano, Bishwa Ranjan Si, Varinder Madhav Verma, Somnath Gupta, Amirali B Bukhari, Suellen Lamb, Konstantinos Konstantopoulos, Gane Ka-Shu Wong, John D Lewis

{"title":"Adrenomedullin 2 drives intratumoral cancer cell invasion, intravasation and metastasis.","authors":"Konstantin Stoletov, Seyedeh Sara Karimian, Douglas Brown, Alice Amitrano, Bishwa Ranjan Si, Varinder Madhav Verma, Somnath Gupta, Amirali B Bukhari, Suellen Lamb, Konstantinos Konstantopoulos, Gane Ka-Shu Wong, John D Lewis","doi":"10.1038/s41388-026-04012-3","DOIUrl":"https://doi.org/10.1038/s41388-026-04012-3","url":null,"abstract":"Cancer cell intravasation requires both directed invasion toward the vasculature and access to functional blood vessels that act as intravasation sites. Using intravital video microscopy, we identified the peptide hormone adrenomedullin 2 (ADM2) as a critical regulator of this process. ADM2 was selectively upregulated in a highly invasive subpopulation of cancer cells that localize near blood vessels and actively drive intravasation. Knockdown of ADM2 significantly impaired intratumoral cancer cell invasion and intravasation in a chicken embryo metastasis model and in vitro. ADM2-deficient tumors exhibited reduced vascularization, limiting the availability of competent intravasation sites. Moreover, loss of ADM2 suppressed the formation of invasive metastatic lesions, indicating a requirement for ADM2 at multiple stages of the metastatic cascade. Consistently, targeting ADM2 in a mouse metastasis model inhibited the development of large intratumoral blood vessels and reduced metastasis. Collectively, these findings establish ADM2 as a previously unrecognized regulator of tumor-vascular interactions and highlight its potential as a therapeutic target to simultaneously disrupt invasion, vascular support, and metastatic dissemination.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170904","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}

引用次数: 0

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