IF 6.9 1区医学

Oncogene Pub Date : 2024-12-20 DOI: 10.1038/s41388-024-03252-5

Sayanika Dutta, Hamed Khedmatgozar, Girijesh Kumar Patel, Daniel Latour, Jonathan Welsh, Mainak Mustafi, Antonina Mitrofanova, Manisha Tripathi, Srinivas Nandana

{"title":"A TBX2-driven signaling switch from androgen receptor to glucocorticoid receptor confers therapeutic resistance in prostate cancer.","authors":"Sayanika Dutta, Hamed Khedmatgozar, Girijesh Kumar Patel, Daniel Latour, Jonathan Welsh, Mainak Mustafi, Antonina Mitrofanova, Manisha Tripathi, Srinivas Nandana","doi":"10.1038/s41388-024-03252-5","DOIUrl":"https://doi.org/10.1038/s41388-024-03252-5","url":null,"abstract":"Recent studies suggest that glucocorticoid receptor (GR) activation can cause enzalutamide resistance in advanced prostate cancer (PCa) via functional bypass of androgen receptor (AR) signaling. However, the specific molecular mechanism(s) driving this process remain unknown. We have previously reported that the transcription factor TBX2 is over-expressed in castrate-resistant prostate cancer (CRPC). In this study, using human PCa and CRPC cell line models, we demonstrate that TBX2 downregulates AR and upregulates GR through direct transcriptional regulation. TBX2 also activated the GR via TBX2-GR protein-protein interactions. Together, TBX2-driven repression of AR and activation of GR resulted in enzalutamide resistance. Our laboratory findings are supported by clinical samples, which show a similar and consistent pattern of transcriptional activity among TBX2, AR and GR across patient cohorts. Notably, we report that SP2509, an allosteric inhibitor of the demethylase-independent function of LSD1 (a TBX2-interacting protein in the COREST complex) disrupts both TBX2-LSD1 and TBX2-GR protein-protein interactions, revealing a unique mode of SP2509 action in CRPC. Taken together, our study identifies the TBX2-driven AR- to GR- signaling switch as a molecular mechanism underlying enzalutamide resistance and provides key insights into a potential therapeutic approach for targeting this switch by disrupting TBX2-GR and TBX2-LSD1 protein-protein interactions.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865047","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

PRMT5-regulated splicing of DNA repair genes drives chemoresistance in breast cancer stem cells.

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.

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

Editorial Expression of Concern: DCAF12 promotes apoptosis and inhibits NF-κB activation by acting as an endogenous antagonist of IAPs.

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-13 DOI: 10.1038/s41388-024-03258-z

Dongyue Jiao, Yingji Chen, Yalan Wang, Huiru Sun, Qing Shi, Liang Zhang, Xiaying Zhao, Yajuan Liu, Huiying He, Zeheng Lv, Chuan Liu, Pingzhao Zhang, Kun Gao, Yan Huang, Yao Li, Liang Li, Chenji Wang

引用次数: 0

Editorial Expression of Concern: Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. 社论表达关注：低氧诱导因子-1α在调节细胞凋亡抵抗中的作用。

IF 6.9 1区医学

Oncogene Pub Date : 2024-12-12 DOI: 10.1038/s41388-024-03257-0

M Kilic, H Kasperczyk, S Fulda, K-M Debatin

引用次数: 0

Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer.

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

Frequent copy number gain of MCL1 is a therapeutic target for osteosarcoma.

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

Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1.

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

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