{"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":"10.1038/s41388-025-03435-8","url":null,"abstract":"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.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 30","pages":"2620-2633"},"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":"10.1038/s41388-025-03421-0","url":null,"abstract":"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.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 30","pages":"2604-2619"},"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 J. 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 J. Oliveira, Carole Grasso, Michael V. Berridge, Renata Zobalova, Miroslava Anderova, Jiri Neuzil","doi":"10.1038/s41388-025-03429-6","DOIUrl":"10.1038/s41388-025-03429-6","url":null,"abstract":"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.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 30","pages":"2588-2603"},"PeriodicalIF":6.9,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-025-03429-6.pdf","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":"OA","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":"10.1038/s41388-025-03391-3","url":null,"abstract":"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.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 29","pages":"2547-2560"},"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":"10.1038/s41388-025-03430-z","url":null,"abstract":"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:Trp53loxP/loxP 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.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 30","pages":"2574-2587"},"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}
OncogenePub Date : 2025-05-02DOI: 10.1038/s41388-025-03423-y
M. Ceccon, M. E. Boggio Merlo, L. Mologni, T. Poggio, L. M. Varesio, M. Menotti, S. Bombelli, R. Rigolio, A. D. Manazza, F. Di Giacomo, C. Ambrogio, G. Giudici, C. Casati, C. Mastini, M. Compagno, S. D. Turner, C. Gambacorti-Passerini, R. Chiarle, C. Voena
{"title":"Correction: Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency","authors":"M. Ceccon, M. E. Boggio Merlo, L. Mologni, T. Poggio, L. M. Varesio, M. Menotti, S. Bombelli, R. Rigolio, A. D. Manazza, F. Di Giacomo, C. Ambrogio, G. Giudici, C. Casati, C. Mastini, M. Compagno, S. D. Turner, C. Gambacorti-Passerini, R. Chiarle, C. Voena","doi":"10.1038/s41388-025-03423-y","DOIUrl":"10.1038/s41388-025-03423-y","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 20","pages":"1545-1545"},"PeriodicalIF":6.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-025-03423-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939687","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 : 2025-05-02DOI: 10.1038/s41388-025-03420-1
John Maringa Githaka, Raven Kirschenman, Namrata Patel, Namita Tripathi, Joy Wang, Laiji Li, Heather Muranyi, Leila Pirayeshfard, Rachel Montpetit, Darryl D. Glubrecht, E. Paul Lerner, Troy Perry, Nika N. Danial, P. Nick Nation, Roseline Godbout, Ing Swie Goping
{"title":"Multiple anti-tumor programs are activated by blocking BAD phosphorylation","authors":"John Maringa Githaka, Raven Kirschenman, Namrata Patel, Namita Tripathi, Joy Wang, Laiji Li, Heather Muranyi, Leila Pirayeshfard, Rachel Montpetit, Darryl D. Glubrecht, E. Paul Lerner, Troy Perry, Nika N. Danial, P. Nick Nation, Roseline Godbout, Ing Swie Goping","doi":"10.1038/s41388-025-03420-1","DOIUrl":"10.1038/s41388-025-03420-1","url":null,"abstract":"The Bcl-2 family member BAD is a candidate disease modulator because it stimulates apoptosis in a cell context basis and inhibits cell migration during normal mammary gland morphogenesis. This activity depends on 3 key regulatory serines (S75, 99, 118) in the unphosphorylated state. Given that developmental programs are often hijacked in cancer, we hypothesized that BAD would impede breast cancer progression. We generated breast cancer mouse models representing loss-of-function or phosphorylation deficient mutations (PyMT-Bad−/− and PyMT-Bad3SA/3SA, respectively). Preventing BAD phosphorylation significantly decreased breast cancer progression and metastasis. The knock-out phenocopied the control PyMT-Bad+/+ suggesting that phosphorylated BAD protein was inert. Thus, the BAD3SA mutation unmasked latent anti-tumor activity. Indeed, transcriptomics showed PyMT-Bad3SA/3SA activated multiple anti-tumor programs including apoptosis, inflammation, cellular differentiation, and diminished cell migration. This anti-tumor effect associated with clinical survival of breast cancer patients whose tumors had high levels of unphosphorylated BAD. Kinase screens identified ERK as the major BAD kinase in breast cells, and ERK inhibition impeded tumoroid invasion. Our data suggest that unphosphorylated BAD modulates anti-tumor pathways that contribute to excellent patient prognosis. Thus, targeting ERK to dephosphorylate BAD may be an exciting therapeutic opportunity in the future.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 29","pages":"2530-2546"},"PeriodicalIF":6.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023571","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}