OncogenePub Date : 2025-05-16DOI: 10.1038/s41388-024-03263-2
Yanxia Jiang, Dexiang Ji, Wen Chen, Yuanzhe Zhu, Ming Luo, Rui Zou, Yilun Fu, Ping Huang, Qing Shi, Dejie Wang, Zhiwang Song
{"title":"Phosphorylation of USP32 by CDK5 regulates Rap1 stability and therapeutic resistance in pancreatic ductal adenocarcinoma.","authors":"Yanxia Jiang, Dexiang Ji, Wen Chen, Yuanzhe Zhu, Ming Luo, Rui Zou, Yilun Fu, Ping Huang, Qing Shi, Dejie Wang, Zhiwang Song","doi":"10.1038/s41388-024-03263-2","DOIUrl":"https://doi.org/10.1038/s41388-024-03263-2","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal human cancer. Gemcitabine-based chemotherapy remains the cornerstone for advanced PDAC. However, resistance to chemotherapy greatly limits its clinical therapeutic efficacy. Accordingly, the identification of novel therapeutic targets to overcome chemoresistance and improve prognosis is urgently needed. Screening of deubiquitinase family members, tandem affinity purification, mass spectrometry, and RNA sequencing (RNA-Seq) analysis were performed to predict the interactions and function of the CDK5-USP32-Rap1 axis in PDAC. In vitro and in vivo experiments were performed to elucidate the regulatory mechanism and biological roles of this axis in glycolytic reprogramming and chemoresistance in PDAC. Finally, TCGA database analysis and immunohistochemistry were performed to determine the expression and clinical significance of CDK5, USP32, and Rap1 in PDAC tissues. USP32 was identified as a bona fide deubiquitinase of Rap1. USP32 deubiquitinates and stabilizes Rap1, thereby promoting glycolytic reprogramming and chemoresistance in PDAC cells. Moreover, we unexpectedly found that CDK5-mediated phosphorylation of USP32 is required for its deubiquitinase activity toward Rap1 and drives malignant phenotypes of PDAC. Additionally, these functions can be significantly inhibited by pharmacological inhibition (roscovitine) or genetic ablation of CDK5. Importantly, combining a CDK5 inhibitor with gemcitabine has a synergetic anticancer effect. Indeed, the effectiveness of targeting CDK5 to sensitize PDAC cells to gemcitabine was confirmed in a patient-derived xenograft (PDX) model. CDK5 and USP32 expression is markedly elevated in PDAC samples and positively associated with Rap1 expression. Increased expression of CDK5, USP32, and Rap1 is significantly associated with poorer prognosis in PDAC. We identified the previously unrecognized oncogenic function and clinical importance of the CDK5-USP32-Rap1 axis, providing preclinical evidence for potential new combination strategies for PDAC therapy.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086157","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}
{"title":"Derlin-3 manipulates the endoplasmic reticulum stress and IgG4 secretion of plasma cells in lung adenocarcinoma.","authors":"Lanlan Lin, Luyang Chen, Guofu Lin, Xiaohui Chen, Linlin Huang, Jiansheng Yang, Shaohua Chen, Ronghang Lin, Dongyong Yang, Fei He, Danwen Qian, Yiming Zeng, Yuan Xu","doi":"10.1038/s41388-025-03435-8","DOIUrl":"https://doi.org/10.1038/s41388-025-03435-8","url":null,"abstract":"<p><p>Derlin-3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, its potential biomechanisms in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains to be elucidated. In the present study, we found that Derlin-3 was predominantly elevated in LUAD tissues, and could predict worse prognosis of LUAD patients. ScRNA-seq analysis indicated that Derlin-3 was mainly enriched in B lymphocytes in the TME, especially in plasma cells. Moreover, Derlin-3 may be involved in ER stress and IgG4 secretion in plasma cells by targeting Hrd1/p38/PRDM1 pathway. While the aberrant IgG4 production may be an essential driver of the polarization of macrophages towards the M2 phenotype. Additionally, downregulation of Derlin-3 could inhibit plasma cells infiltration and M2 macrophage polarization in vivo. Our results indicated that Derlin-3 could shape TME via ER stress to harness immune function, which might serve as a promising immunotherapeutic target in LUAD.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079354","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}
OncogenePub Date : 2025-05-08DOI: 10.1038/s41388-025-03421-0
Jiao Tian, Chaoge Liu, Bing Li, Ning Hu, Xiaoting Gu, Dongmei Li, Xiaoyu Ai, Honggang Zhou, Ting Xiao, Cheng Yang
{"title":"PAR1 inhibition sensitizes HPV-negative HNSCC cells to ferroptosis through inhibition of the STAT3-mediated regulation of iron and lipid metabolic pathways.","authors":"Jiao Tian, Chaoge Liu, Bing Li, Ning Hu, Xiaoting Gu, Dongmei Li, Xiaoyu Ai, Honggang Zhou, Ting Xiao, Cheng Yang","doi":"10.1038/s41388-025-03421-0","DOIUrl":"https://doi.org/10.1038/s41388-025-03421-0","url":null,"abstract":"<p><p>Ferroptosis, a cell death mechanism characterized by the accumulation of lipid peroxides and subsequent membrane disruption, is emerging as a promising strategy for cancer treatment. However, many tumors, including head and neck squamous cell carcinoma (HNSCC), show resistance to ferroptosis, which reduces its therapeutic effect. Protease-activated receptors (PARs) are highly expressed in many tumors and are closely associated with tumor progression. Our study showed that the expression of protease-activated receptor 1 (PAR1) was downregulated during ferroptosis in HPV-negative HNSCC. Further studies showed that downregulation of PAR1 expression could enhance the therapeutic effect of Erastin on HPV-negative HNSCC, where PAR1 regulated the expression levels of SLC7A11, GPX4, and FTH1. In addition, we found that PAR1 activated the JAK2/STAT3 pathway in a Rac-1-dependent manner and identified STAT3 as a critical transcription factor in PAR1-mediated HPV-negative HNSCC progression and ferroptosis regulation. Inhibition of STAT3 expression attenuated the tumorigenicity of PAR1. It is worth noting that the PAR1 small molecule inhibitor Vorapaxar can further enhance the therapeutic effect of Erastin on HPV-negative HNSCC. Therefore, we propose that PAR1 participates in the progression of HPV-negative HNSCC through STAT3 and reduces the sensitivity of HPV-negative HNSCC to ferroptosis, providing a new perspective for discovering ferroptosis regulatory factors.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014400","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}
OncogenePub Date : 2025-05-08DOI: 10.1038/s41388-025-03436-7
L. Dong, C. C. Jiang, R. F. Thorne, A. Croft, F. Yang, H. Liu, C. E. de Bock, P. Hersey, X. D. Zhang
{"title":"Editorial Expression of Concern: Ets-1 mediates upregulation of Mcl-1 downstream of XBP-1 in human melanoma cells upon ER stress","authors":"L. Dong, C. C. Jiang, R. F. Thorne, A. Croft, F. Yang, H. Liu, C. E. de Bock, P. Hersey, X. D. Zhang","doi":"10.1038/s41388-025-03436-7","DOIUrl":"10.1038/s41388-025-03436-7","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 21","pages":"1662-1662"},"PeriodicalIF":6.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-025-03436-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
OncogenePub Date : 2025-05-05DOI: 10.1038/s41388-025-03429-6
Petra Brisudova, Dana Stojanovic, Jaromir Novak, Zuzana Nahacka, Gabriela Lopes Oliveira, Ondrej Vanatko, Sarka Dvorakova, Berwini Endaya, Jaroslav Truksa, Monika Kubiskova, Alice Foltynova, Daniel Jirak, Natalia Jirat-Ziolkowska, Lukas Kucera, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Paulo Oliveira, Carole Grasso, Michael V Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil
{"title":"Functional mitochondrial respiration is essential for glioblastoma tumour growth.","authors":"Petra Brisudova, Dana Stojanovic, Jaromir Novak, Zuzana Nahacka, Gabriela Lopes Oliveira, Ondrej Vanatko, Sarka Dvorakova, Berwini Endaya, Jaroslav Truksa, Monika Kubiskova, Alice Foltynova, Daniel Jirak, Natalia Jirat-Ziolkowska, Lukas Kucera, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Paulo Oliveira, Carole Grasso, Michael V Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil","doi":"10.1038/s41388-025-03429-6","DOIUrl":"https://doi.org/10.1038/s41388-025-03429-6","url":null,"abstract":"<p><p>Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007986","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}
OncogenePub Date : 2025-05-03DOI: 10.1038/s41388-025-03391-3
Annika M A Berends, René Wardenaar, Hilda van den Bos, Andréa E Tijhuis, Thera P Links, Richard A Feelders, Leo J Hofland, Schelto Kruijff, Karel Pacak, Diana C J Spierings, Michiel N Kerstens, Floris Foijer
{"title":"Single-cell chromosome and bulk transcriptome analysis as a diagnostic tool to differentiate between localized and metastatic pheochromocytoma and sympathetic paraganglioma.","authors":"Annika M A Berends, René Wardenaar, Hilda van den Bos, Andréa E Tijhuis, Thera P Links, Richard A Feelders, Leo J Hofland, Schelto Kruijff, Karel Pacak, Diana C J Spierings, Michiel N Kerstens, Floris Foijer","doi":"10.1038/s41388-025-03391-3","DOIUrl":"https://doi.org/10.1038/s41388-025-03391-3","url":null,"abstract":"<p><p>Approximately 10-20% of patients with pheochromocytoma or sympathetic paraganglioma (PPGL) develop metastatic disease, most often as metachronous lesions. Unfortunately, there is a lack of accurate biomarkers that can predict the biologic behavior of a PPGL at the initial diagnosis. We investigated tumor samples from patients with PPGL and a diagnosis of either localized or metastatic disease with synchronous or metachronous metastases and performed a comprehensive molecular analysis through application of single-cell whole-genome sequencing and bulk transcriptome analysis, including variant detection analysis of RNA sequences. We found that PPGL displayed complex karyotypes with recurrent aneuploidies and substantial cell-to-cell karyotype variability, indicating ongoing chromosomal instability (CIN) in both localized and metastatic tumors. Transcriptome analysis on the other hand revealed several differences between localized and metastatic PPGL including TNFα and TGFβ signaling in metastatic PPGL that were already detectable in primary tumor samples of initially non-metastatic-appearing PPGLs that developed metachronous metastases. Altogether our findings indicate that while localized and metastatic PPGL in general have comparable genomic landscapes, they do show transcriptional differences that are already detectable in primary tumor PPGL before development of metastases. This finding could provide an important tool for improvement of patient stratification at initial diagnosis.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038930","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}
{"title":"Loss of NUMB promotes hepatomegaly and hepatocellular carcinoma through the AKT/glycogen/hippo signaling.","authors":"Yuke Shu, Qing Tao, Qing Xu, Yuwei Chen, Yahong Xu, Tingting Ma, Zhiqi Zhu, Xinyu Wei, Fei Liu, Zhenru Wu, Yuting Zeng, Menglin Chen, Mingyang Shao, Xiaoyue Cao, Yongjie Zhou, Wei Peng, Chuan Li, Yujun Shi","doi":"10.1038/s41388-025-03430-z","DOIUrl":"https://doi.org/10.1038/s41388-025-03430-z","url":null,"abstract":"<p><p>Excessive glycogen deposition is a common feature of liver enlargement, liver adenoma, and liver cancer, yet the underlying mechanisms remain poorly understood. In this study, we found that NUMB, a well-known cell fate determinant, is downregulated in glycogen-rich adenomas and hepatocellular carcinoma (HCC). NUMB-deficient livers developed excessive glycogen accumulation and adenoma formation particularly in aged mice. Surprisingly, the Alb-Cre:Trp53<sup>loxP/loxP</sup> liver displayed no similar defective morphology and function, although p53 is considered an important downstream target of NUMB and closely related to glucose metabolism. Instead, we observed a synergistic interaction between NUMB and p53 in regulating glycogen metabolism in HCC tissues and cell lines. Combined knockout of NUMB and p53 in mice significantly enhances glycogen accumulation and hepatomegaly, particularly when mice are subjected to a high sugar diet (HSD), leading to higher cancer incidence. Mechanistically, NUMB deficiency disrupts the PTEN-PI3K/AKT signaling pathway, promoting glycogen accumulation. Subsequently, successive glycogen deposition triggers hepatomegaly and tumorigenesis via the Hippo signaling pathway. Our results suggest that NUMB plays a crucial role in maintaining the homeostasis of glucose metabolism and suppressing the development of liver tumors associated with glycogen deposition.</p>","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022253","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}
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