Oncogene最新文献_第4页

PRMT5-regulated splicing of DNA repair genes drives chemoresistance in breast cancer stem cells. prmt5调控的DNA修复基因剪接驱动乳腺癌干细胞的化疗耐药。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-18 DOI: 10.1038/s41388-024-03264-1

Matthew S Gillespie, Kelly Chiang, Gemma L Regan-Mochrie, Soo-Youn Choi, Ciara M Ward, Debashish Sahay, Paloma Garcia, Roland Arnold, Clare C Davies

{"title":"PRMT5-regulated splicing of DNA repair genes drives chemoresistance in breast cancer stem cells.","authors":"Matthew S Gillespie, Kelly Chiang, Gemma L Regan-Mochrie, Soo-Youn Choi, Ciara M Ward, Debashish Sahay, Paloma Garcia, Roland Arnold, Clare C Davies","doi":"10.1038/s41388-024-03264-1","DOIUrl":"https://doi.org/10.1038/s41388-024-03264-1","url":null,"abstract":"Breast cancer stem cells (BCSCs) are a rare cell population that is responsible for tumour initiation, metastasis and chemoresistance. Despite this, the mechanism by which BCSCs withstand genotoxic stress is largely unknown. Here, we uncover a pivotal role for the arginine methyltransferase PRMT5 in mediating BCSC chemoresistance by modulating DNA repair efficiency. Mechanistically, we identify PRMT5 as a major regulator of DNA damage response (DDR) gene splicing in BCSCs, particularly those integral to the Fanconi Anaemia and homologous recombination pathways, with PRMT5 inhibition synergising with chemotherapy to promote BCSC apoptosis. A comparison of BCSCs and their bulk cell progeny identified some shared (ATM, DDX11, EXO1, FAN1, SLX4) but many unique (ATR, RAD17, RAD51D, RUVBL1) PRMT5-dependent alternative DDR splicing events. Surprisingly, these skipped exons and retained intron events rarely lead to substantial gene expression repression, suggesting that PRMT5 inhibition predominantly results in nuclear detention of intron-containing transcripts and the production of non-canonical isoforms with compromised protein function. Since many genes within the same DDR pathway undergo deregulated splicing, this study thus reveals additional points of vulnerability and alternative combination drug strategies that could improve the therapeutic efficacy of PRMT5 inhibitors to promote BCSC eradication.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854721","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

Identification of novel germline mutations in FUT7 and EXT1 linked with hereditary multiple exostoses. 鉴定出与遗传性多发性骨质疏松症有关的 FUT7 和 EXT1 基因突变。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-17 DOI: 10.1038/s41388-024-03254-3

Wan Peng, Gao-Fei Li, Guo-Wang Lin, Xi-Xi Cheng, Xiao-Yu Zuo, Qiao-Hong Lin, Shu-Qiang Liu, De-Jun Li, Dao-Chao Lin, Jun-Qiang Yin, Chun-Ling Luo, Yi-Yue Zhang, Xian-Biao Xie, Jin-Xin Bei

{"title":"Identification of novel germline mutations in FUT7 and EXT1 linked with hereditary multiple exostoses.","authors":"Wan Peng, Gao-Fei Li, Guo-Wang Lin, Xi-Xi Cheng, Xiao-Yu Zuo, Qiao-Hong Lin, Shu-Qiang Liu, De-Jun Li, Dao-Chao Lin, Jun-Qiang Yin, Chun-Ling Luo, Yi-Yue Zhang, Xian-Biao Xie, Jin-Xin Bei","doi":"10.1038/s41388-024-03254-3","DOIUrl":"https://doi.org/10.1038/s41388-024-03254-3","url":null,"abstract":"Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847081","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

Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer. 线粒体未折叠蛋白反应依赖的β-catenin信号促进神经内分泌性前列腺癌的发生。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-17 DOI: 10.1038/s41388-024-03261-4

Jordan Alyse Woytash, Rahul Kumar, Ajay K Chaudhary, Cullan Donnelly, Adam Wojtulski, Murali Bethu, Jianmin Wang, Joseph Spernyak, Peter Bross, Neelu Yadav, Joseph R Inigo, Dhyan Chandra

{"title":"Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.","authors":"Jordan Alyse Woytash, Rahul Kumar, Ajay K Chaudhary, Cullan Donnelly, Adam Wojtulski, Murali Bethu, Jianmin Wang, Joseph Spernyak, Peter Bross, Neelu Yadav, Joseph R Inigo, Dhyan Chandra","doi":"10.1038/s41388-024-03261-4","DOIUrl":"https://doi.org/10.1038/s41388-024-03261-4","url":null,"abstract":"The mitochondrial unfolded protein response (UPRmt) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPRmt in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPRmt in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPRmt heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPRmt. We discovered that UPRmt promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPRmt resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPRmt promotes mitochondrial health via upregulating β-catenin signaling and UPRmt represents viable therapeutic target for NEPC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847084","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

Lack of dominant-negative activity for tumor-related ZNRF3 missense mutations at endogenous levels. 在内源性水平上缺乏与肿瘤相关的ZNRF3错义突变的显性负活性。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-14 DOI: 10.1038/s41388-024-03253-4

Shanshan Li, Jiahui Niu, Ruyi Zhang, Sanne Massaar, Madalena Neves Cabrita, Jenna van Merode, Nicky de Schipper, Lisa van de Kamp, Maikel P Peppelenbosch, Ron Smits

{"title":"Lack of dominant-negative activity for tumor-related ZNRF3 missense mutations at endogenous levels.","authors":"Shanshan Li, Jiahui Niu, Ruyi Zhang, Sanne Massaar, Madalena Neves Cabrita, Jenna van Merode, Nicky de Schipper, Lisa van de Kamp, Maikel P Peppelenbosch, Ron Smits","doi":"10.1038/s41388-024-03253-4","DOIUrl":"https://doi.org/10.1038/s41388-024-03253-4","url":null,"abstract":"ZNRF3, a negative regulator of β-catenin signaling, removes Wnt receptors from the membrane. Currently, it is unknown which tumor-associated variants can be considered driver mutations and through which mechanisms they contribute to cancer. Here we show that all truncating mutations analyzed at endogenous levels exhibit loss-of-function, with longer variants retaining partial activity. Regarding missense mutations, we show that 27/82 ZNRF3 variants in the RING and R-Spondin domain structures, lead to (partial) loss-of-function/hyperactivation. Mechanistically, defective R-Spondin domain variants appear to undergo endoplasmic-reticulum-associated degradation due to protein misfolding, leading to reduced protein levels. They fail to reach the membrane correctly, which can be partially restored for several variants by culturing cells at 27 °C. Although RING and R-Spondin domain mutations in RNF43/ZNRF3 are often considered to possess dominant-negative oncogene-like activity in cancers, our findings challenge this notion. When representative variants are heterozygously introduced into endogenous ZNRF3, their impact on β-catenin signaling mirrors that of heterozygous knockout, suggesting that the supposed dominant-negative effect is non-existent. In other words, so-called \"hyperactivating\" ZNRF3/RNF43 mutations behave as classical loss-of-function mutations at endogenous levels.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824116","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

Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer. SIRT1在胃癌h19糖酵解-组蛋白乳酸化正反馈回路中的脱乙酰酶作用。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-11 DOI: 10.1038/s41388-024-03243-6

Shu Tsukihara, Yoshimitsu Akiyama, Shu Shimada, Megumi Hatano, Yosuke Igarashi, Tomohiko Taniai, Yoshiaki Tanji, Keita Kodera, Koya Yasukawa, Kentaro Umeura, Atsushi Kamachi, Atsushi Nara, Keisuke Okuno, Masanori Tokunaga, Hiroto Katoh, Shumpei Ishikawa, Toru Ikegami, Yusuke Kinugasa, Ken Eto, Shinji Tanaka

{"title":"Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer.","authors":"Shu Tsukihara, Yoshimitsu Akiyama, Shu Shimada, Megumi Hatano, Yosuke Igarashi, Tomohiko Taniai, Yoshiaki Tanji, Keita Kodera, Koya Yasukawa, Kentaro Umeura, Atsushi Kamachi, Atsushi Nara, Keisuke Okuno, Masanori Tokunaga, Hiroto Katoh, Shumpei Ishikawa, Toru Ikegami, Yusuke Kinugasa, Ken Eto, Shinji Tanaka","doi":"10.1038/s41388-024-03243-6","DOIUrl":"https://doi.org/10.1038/s41388-024-03243-6","url":null,"abstract":"Histone lactylation, a novel epigenetic modification, is regulated by the lactate produced by glycolysis. Glycolysis is activated in various cancers, including gastric cancer (GC). However, the molecular mechanism and clinical impact of histone lactylation in GC remain poorly understood. Here, we demonstrate that histone H3K18 lactylation (H3K18la) is elevated in GC, correlating with a worse prognosis. SIRT1 overexpression decreases H3K18la levels, whereas SIRT1 knockdown increases H3K18la levels in GC cells. RNA-seq analysis demonstrates that lncRNA H19 is markedly downregulated in GC cells with SIRT1 overexpression and those grown under glucose free condition, which confirmed decreased H3K18la levels at its promoter region. H19 knockdown decreased the expression levels of LDHA and H3K18la, and LDHA knockdown impaired H19 and H3K18la expression, suggesting an H19/glycolysis/H3K18la-positive feedback loop. Combined treatment with low doses of the SIRT1-specific activator SRT2104 and the LDHA inhibitor oxamate exerted significant antitumor effects on GC cells, with limited adverse effects on normal gastric cells. The SIRT1-weak/H3K18la-strong signature was found to be an independent prognostic factor in patients with GC. Therefore, SIRT1 acts as a histone delactylase for H3K18, and loss of SIRT1 triggers a positive feedback loop involving H19/glycolysis/H3K18la. Targeting this pathway serves as a novel therapeutic strategy for GC treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807685","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

Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1. 特发性肺纤维化中衰老的肺成纤维细胞通过分泌外泌体MMP1促进非小细胞肺癌的进展。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-11 DOI: 10.1038/s41388-024-03236-5

Yuqiong Lei, Cheng Zhong, Jingyuan Zhang, Qi Zheng, Yongle Xu, Zhoubin Li, Chenwen Huang, Tao Ren

{"title":"Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1.","authors":"Yuqiong Lei, Cheng Zhong, Jingyuan Zhang, Qi Zheng, Yongle Xu, Zhoubin Li, Chenwen Huang, Tao Ren","doi":"10.1038/s41388-024-03236-5","DOIUrl":"https://doi.org/10.1038/s41388-024-03236-5","url":null,"abstract":"Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. Current treatments are insufficient in improving the prognosis of lung cancer patients with comorbid idiopathic pulmonary fibrosis (IPF-LC). Senescent fibroblasts, as stromal cells in the tumor microenvironment, influence tumor progression via exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we investigated the impact of senescent IPF lung fibroblast (diseased human lung fibroblasts, DHLF)-derived exosomes on non-small cell lung cancer (NSCLC). We found DHLF expressed significant senescence markers, and promoted NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, senescent DHLF showed strong secretion of exosomes, and these exosomes enhanced the proliferation and colony-forming ability of cancer cells. Proteomic analysis showed DHLF-derived exosomes exhibited upregulated senescence-associated secretory phenotype (SASP) factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-derived exosomes in vivo and in vitro. Mechanistically, MMP1 acted by activating the PI3K-AKT-mTOR pathway. In conclusion, our results suggest that exosomal MMP1 derived from senescent IPF fibroblasts promotes NSCLC proliferation and colony formation by targeting PAR1 and activating the PI3K-AKT-mTOR pathway. These findings provide a novel therapeutic approach for patients with IPF-LC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813817","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

Frequent copy number gain of MCL1 is a therapeutic target for osteosarcoma. 频繁的MCL1拷贝数增加是骨肉瘤的治疗靶点。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-11 DOI: 10.1038/s41388-024-03251-6

Satoshi Takagi, Mikako Nakajima, Sumie Koike, Miho Takami, Yoshiya Sugiura, Seiji Sakata, Satoko Baba, Ai Takemoto, Tianyi Huang, Yosuke Seto, Masanori Saito, Yuki Funauchi, Keisuke Ae, Kengo Takeuchi, Naoya Fujita, Ryohei Katayama

{"title":"Frequent copy number gain of MCL1 is a therapeutic target for osteosarcoma.","authors":"Satoshi Takagi, Mikako Nakajima, Sumie Koike, Miho Takami, Yoshiya Sugiura, Seiji Sakata, Satoko Baba, Ai Takemoto, Tianyi Huang, Yosuke Seto, Masanori Saito, Yuki Funauchi, Keisuke Ae, Kengo Takeuchi, Naoya Fujita, Ryohei Katayama","doi":"10.1038/s41388-024-03251-6","DOIUrl":"https://doi.org/10.1038/s41388-024-03251-6","url":null,"abstract":"Osteosarcoma (OS) is a primary malignant bone tumor primarily affecting children and adolescents. The lack of progress in drug development for OS is partly due to unidentified actionable oncogenic drivers common to OS. In this study, we demonstrate that copy number gains of MCL1 frequently occur in OS, leading to vulnerability to therapies based on Mcl-1 inhibitors. Fluorescence in situ hybridization analysis of 41 specimens revealed MCL1 amplification in 46.3% of patients with OS. Genetic inhibition of MCL1 induced significant apoptosis in MCL1-amplified OS cells, and the pharmacological efficacy of Mcl-1 inhibitors was correlated with MCL1 copy numbers. Chromosome 1q21.2-3 region, where MCL1 is located, contains multiple genes related to the IGF-1R/PI3K pathway, including PIP5K1A, TARS2, OUTD7B, and ENSA, which also showed increased copy numbers in MCL1-amplified OS cells. Furthermore, combining Mcl-1 inhibitors with IGF-1R inhibitors resulted in synergistic cell death by overcoming drug tolerance conferred by the activation of IGF signaling and suppressed tumor growth in MCL1-amplified OS xenograft models. These results suggest that genomic amplification of MCL1 in the 1q21.2-3 region, which occurred in approximately half of OS patients, may serve as a predictive biomarker for the combination therapy with an Mcl-1 inhibitor and an IGF1R inhibitor.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813816","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

Tissue factor promotes TREX1 protein stability to evade cGAS-STING innate immune response in pancreatic ductal adenocarcinoma. 组织因子促进TREX1蛋白稳定性以逃避胰腺导管腺癌的cGAS-STING先天免疫反应。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-10 DOI: 10.1038/s41388-024-03248-1

Yinyin Xue, Yue Wang, Zhiqiang Ren, Ker Yu

{"title":"Tissue factor promotes TREX1 protein stability to evade cGAS-STING innate immune response in pancreatic ductal adenocarcinoma.","authors":"Yinyin Xue, Yue Wang, Zhiqiang Ren, Ker Yu","doi":"10.1038/s41388-024-03248-1","DOIUrl":"https://doi.org/10.1038/s41388-024-03248-1","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains the most challenging human malignancy that urgently needs effective therapy. Tissue factor (TF) is expressed in ~80% of PDAC and represents a potential therapeutic target. While a novel TF-ADC (MRG004A) demonstrated efficacy for PDAC and TNBC in a Phase I/II trial [Ref. 18], the functional role of TF in PDAC remains incompletely understood. We investigated the relationship between TF and the innate STING pathway. We found that patients with TF-overexpression had poor survival, very low levels of P-STING/P-TBK1, reduced amounts of ISGs and chemokines as well as low numbers of cytotoxic immunocytes in their tumor. In experimental models of mouse and human PDAC, tumor cell-intrinsic TF expression played a major role in silencing the cytosolic micronuclei sensing and cGAS-STING activation. This process involved a TREX1 exonuclease-dependent clearance of micronucleus-DNA accumulated in tumor cells. Treatment of tumors with TF-KO/shRNA or anti-TF antibody HuSC1-39 (parent antibody of MRG004A) triggered a rapid and proteasome-dependent degradation of TREX1 thereby restoring the STING/TBK1 cascade phosphorylation. TF-inhibition therapy promoted a robust STING/IRF3-dependent IFN/CCL5/CXCL9-11 production, immune effector cell infiltration and antitumor efficacy. Moreover, in the PBMC and cancer cell co-culture, TF-inhibition synergized with a STING agonist compound. A covalently conjugated TF antibody-STING agonist ADC strongly increased the efficacy of tumor-targeted STING agonism on chemokine secretion and tumor inhibition in vitro and in vivo. Thus, TF-inhibition reshapes an \"immune hot\" tumor environment. TF-targeted therapy warrants clinical investigation as a single agent or in combination with immunotherapy for treating TF-positive PDAC and TNBC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807690","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

TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma. TFF3驱动肺腺癌中Hippo依赖性EGFR-TKI耐药。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-10 DOI: 10.1038/s41388-024-03244-5

Shuwei Zhang, Yan Qin Tan, Xi Zhang, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E Lobie

{"title":"TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma.","authors":"Shuwei Zhang, Yan Qin Tan, Xi Zhang, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E Lobie","doi":"10.1038/s41388-024-03244-5","DOIUrl":"10.1038/s41388-024-03244-5","url":null,"abstract":"Intrinsic and acquired resistance represent major obstacles to optimize outcomes in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted therapy in lung adenocarcinoma (LUAD). Hence, a deeper understanding of EGFR-TKI resistance mechanisms in LUAD will potentially assist in formulating strategies to delay or overcome such resistance. Herein, it was observed that trefoil factor 3 (TFF3) is a crucial mediator of the LUAD EGFR-TKI response. TFF3 conferred intrinsic resistance to EGFR inhibition in LUAD by promotion of EGFR activation. TFF3 expression was also increased in acquired EGFR-TKI resistant LUAD, accompanied by reduced EGFR activation. YAP, a key mediator of the Hippo signaling, was positively regulated by TFF3 by post-transcriptional mechanisms and was responsible for acquired EGFR-TKI resistance mediated by TFF3. Inhibition of TFF3 by a small molecule inhibitor not only enhanced EGFR-TKI sensitivity in LUAD cells but also restored the sensitivity of acquired EGFR-TKI resistant LUAD cells to EGFR-TKIs in vitro and in vivo. These findings demonstrate a pivotal function of TFF3 in mediating both intrinsic and acquired EGFR-TKI resistance in LUAD and may offer a potential therapeutic mechanism for delaying or overcoming resistance to EGFR-TKIs.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807687","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

Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression. 假激酶TRIB3通过usp10介导的去泛素化来稳定SSRP1，促进多发性骨髓瘤的进展。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-09 DOI: 10.1038/s41388-024-03245-4

Haiqin Wang, Long Liang, Yifang Xie, Han Gong, Feifan Fan, Chengcai Wen, Yu Jiang, Shiying Lei, Xili Qiu, Hongling Peng, Mao Ye, Xiaojuan Xiao, Jing Liu

{"title":"Pseudokinase TRIB3 stabilizes SSRP1 via USP10-mediated deubiquitination to promote multiple myeloma progression.","authors":"Haiqin Wang, Long Liang, Yifang Xie, Han Gong, Feifan Fan, Chengcai Wen, Yu Jiang, Shiying Lei, Xili Qiu, Hongling Peng, Mao Ye, Xiaojuan Xiao, Jing Liu","doi":"10.1038/s41388-024-03245-4","DOIUrl":"https://doi.org/10.1038/s41388-024-03245-4","url":null,"abstract":"Multiple myeloma (MM), the world's second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo. Mechanistically, TRIB3 directly interacts with structure-specific recognition protein 1 (SSRP1) and ubiquitin-specific peptidase 10 (USP10), facilitating the formation of a TRIB3/USP10/SSRP1 ternary complex. This complex stabilizes SSRP1 via USP10-mediated deubiquitination, thereby driving MM cell proliferation. Furthermore, a stapled peptide, SP-A, was developed, which effectively disrupts the TRIB3/USP10/SSRP1 complex, leading to a decrease in SSRP1 levels by inhibiting its stabilization through USP10. Notably, SP-A exhibits strong synergistic effects when combined with the proteasome inhibitor bortezomib. Given the critical role of the TRIB3/USP10/SSRP1 complex in MM pathophysiology, it represents a promising therapeutic target for MM treatment. In MM cells, TRIB3, USP10 and SSRP1 form a ternary complex and TRIB3 enhances the deubiquitinating effect of USP10 on SSRP1, leading to malignant progression of MM. In the case of drug intervention, SP-A attenuates the binding of SSRP1 and USP10 by inhibiting protein interactions between TRIB3 and SSRP1 and promoted SSRP1 protein degradation, leading to significant inhibition of MM development. Visual abstract created with Biorender.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801406","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