Pub Date : 2025-11-20DOI: 10.1038/s41388-025-03624-5
Heidi Pharo, Hege Marie Vedeld, Ingrid Vikan Sjurgard, Rita Pinto, Guro Elisabeth Lind
Global cancer incidence continues to rise, emphasizing the urgent need for improved diagnostics and management strategies. DNA methylation biomarkers in liquid biopsies offer a promising, minimally invasive solution. Despite their potential, only a few tests have successfully transitioned from research to clinical practice. This review addresses key aspects influencing successful biomarker development and clinical implementation—including liquid biopsy source selection, biomarker discovery workflow and targeted validation in clinical sample series—and provide strategies to improve accuracy, reproducibility and clinical utility. Altogether, these considerations could aid in bridging the translational gap from research to clinical application, and to increase the number of clinically implemented liquid biopsy tests.
{"title":"From concept to clinic: a roadmap for DNA methylation biomarkers in liquid biopsies","authors":"Heidi Pharo, Hege Marie Vedeld, Ingrid Vikan Sjurgard, Rita Pinto, Guro Elisabeth Lind","doi":"10.1038/s41388-025-03624-5","DOIUrl":"10.1038/s41388-025-03624-5","url":null,"abstract":"Global cancer incidence continues to rise, emphasizing the urgent need for improved diagnostics and management strategies. DNA methylation biomarkers in liquid biopsies offer a promising, minimally invasive solution. Despite their potential, only a few tests have successfully transitioned from research to clinical practice. This review addresses key aspects influencing successful biomarker development and clinical implementation—including liquid biopsy source selection, biomarker discovery workflow and targeted validation in clinical sample series—and provide strategies to improve accuracy, reproducibility and clinical utility. Altogether, these considerations could aid in bridging the translational gap from research to clinical application, and to increase the number of clinically implemented liquid biopsy tests.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 49","pages":"4814-4831"},"PeriodicalIF":7.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03624-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564862","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}
Bladder cancer (BCa) remains a prevalent malignancy with limited therapeutic options. Although cholesterol elevation links to BCa progression, the specific role of cholesterol metabolism remains unclear. Here, we demonstrate that squalene epoxidase (SQLE), a key cholesterol biosynthesis enzyme, drives BCa oncogenesis. SQLE is upregulated in BCa patients and correlates with poor survival. Functionally, bladder-specific Sqle transgenic (tg) mice showed accelerated tumorigenesis, while Sqle knockout (ko) demonstrated opposite effects in vivo. Mechanistically, SQLE localizes to mitochondria and directly interacts with Lon peptidase 1 (LONP1) to stabilize mitochondrial transcription factor A (TFAM) by preventing its proteolysis, leading to elevated oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mtROS). Pharmacological clearance of mtROS via Mito-TEMPO suppressed tumor growth in Sqle-overexpressing models. Importantly, the FDA-approved SQLE inhibitor terbinafine significantly suppressed BCa progression in preclinical models. Our findings establish SQLE as a critical regulator of mitochondrial metabolism in BCa, supporting SQLE inhibitors as potential therapeutics.
{"title":"SQLE drives bladder cancer progression by boosting mitochondrial oxidative phosphorylation","authors":"Yihong Dong, Xinjian Jiang, Xinxin Yang, Jinfeng Zhang, Qiang Fu, Yunfei Zhou, Xun Yang, Yin Fu, Yunjing Hou, Mujiao Li, Jun Yan, Jianwen Xu, Yujuan Yi, Meijuan Liu, Xiaorui Huo, Jiang Han, Yumeng Wang, Chenxu Guo, Qingxin Zhang, Aodi Wu, Xiaoqing Li, Xiaohan Zhang, Shuyuan Chang, Ayaka Tomii, Lin Jia, Yu Xiao, Xiaoyang Hu, Hongxue Meng, Dabin Liu, Shuijie Li","doi":"10.1038/s41388-025-03626-3","DOIUrl":"10.1038/s41388-025-03626-3","url":null,"abstract":"Bladder cancer (BCa) remains a prevalent malignancy with limited therapeutic options. Although cholesterol elevation links to BCa progression, the specific role of cholesterol metabolism remains unclear. Here, we demonstrate that squalene epoxidase (SQLE), a key cholesterol biosynthesis enzyme, drives BCa oncogenesis. SQLE is upregulated in BCa patients and correlates with poor survival. Functionally, bladder-specific Sqle transgenic (tg) mice showed accelerated tumorigenesis, while Sqle knockout (ko) demonstrated opposite effects in vivo. Mechanistically, SQLE localizes to mitochondria and directly interacts with Lon peptidase 1 (LONP1) to stabilize mitochondrial transcription factor A (TFAM) by preventing its proteolysis, leading to elevated oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mtROS). Pharmacological clearance of mtROS via Mito-TEMPO suppressed tumor growth in Sqle-overexpressing models. Importantly, the FDA-approved SQLE inhibitor terbinafine significantly suppressed BCa progression in preclinical models. Our findings establish SQLE as a critical regulator of mitochondrial metabolism in BCa, supporting SQLE inhibitors as potential therapeutics.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 49","pages":"4796-4813"},"PeriodicalIF":7.3,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03626-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550203","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}
Pub Date : 2025-11-17DOI: 10.1038/s41388-025-03627-2
Lijun Zhou, Mei Liu, Fujun Liu, Zhengkun Wang, Xinyu Li, Xiaoyu Peng, Wenqiang Ma, Peilan Guo, Lifang Yuan, Slawomir Wolczynski, Nafis Ahmed Rahman, Wei Song, Xiangdong Li
Breast cancer (BC) is the most prevalent malignancy among women worldwide. Growing evidence highlights the crucial role of circular RNAs (circRNAs) in BC carcinogenesis; however, their underlying mechanisms remain largely unknown. In this study, we identify circCLASP1, which is significantly upregulated in BC tissues (n = 65) and serum samples (n = 61). Its expression correlates with lymph node metastasis, ki67 expression, and tumor size. Receiver operation characteristic (ROC) curve analysis reveals area under the curve (AUC) values of 0.8196 (BC tissues) and 0.8902 (BC serum), respectively. Functionally, circCLASP1 knockdown significantly suppresses BC cell proliferation, migration, and invasion. Mechanistically, circCLASP1 prevents the ubiquitin-mediated degradation of GLI1 protein by facilitating its interaction with CCT2, thereby stabilizing GLI1. Moreover, circCLASP1 enhances the nuclear accumulation of GLI1, leading to increased SNAIL expression and thereby upregulating the expression of CCL2 and CCL5, which in turn promotes macrophage M2 polarization, ultimately resulting in BC progression and subsequent lung metastasis. Further analysis reveals that U2AF2 regulates circCLASP1 biogenesis. Collectively, these findings demonstrate that circCLASP1 promotes BC progression and an immunosuppressive microenvironment via the CCT2/GLI1/SNAIL axis, highlighting its potential as a prognostic biomarker and therapeutic target for BC.
{"title":"Circular RNA CLASP1 modulates the GLI1/SNAIL axis and enhances macrophage polarization in breast cancer","authors":"Lijun Zhou, Mei Liu, Fujun Liu, Zhengkun Wang, Xinyu Li, Xiaoyu Peng, Wenqiang Ma, Peilan Guo, Lifang Yuan, Slawomir Wolczynski, Nafis Ahmed Rahman, Wei Song, Xiangdong Li","doi":"10.1038/s41388-025-03627-2","DOIUrl":"10.1038/s41388-025-03627-2","url":null,"abstract":"Breast cancer (BC) is the most prevalent malignancy among women worldwide. Growing evidence highlights the crucial role of circular RNAs (circRNAs) in BC carcinogenesis; however, their underlying mechanisms remain largely unknown. In this study, we identify circCLASP1, which is significantly upregulated in BC tissues (n = 65) and serum samples (n = 61). Its expression correlates with lymph node metastasis, ki67 expression, and tumor size. Receiver operation characteristic (ROC) curve analysis reveals area under the curve (AUC) values of 0.8196 (BC tissues) and 0.8902 (BC serum), respectively. Functionally, circCLASP1 knockdown significantly suppresses BC cell proliferation, migration, and invasion. Mechanistically, circCLASP1 prevents the ubiquitin-mediated degradation of GLI1 protein by facilitating its interaction with CCT2, thereby stabilizing GLI1. Moreover, circCLASP1 enhances the nuclear accumulation of GLI1, leading to increased SNAIL expression and thereby upregulating the expression of CCL2 and CCL5, which in turn promotes macrophage M2 polarization, ultimately resulting in BC progression and subsequent lung metastasis. Further analysis reveals that U2AF2 regulates circCLASP1 biogenesis. Collectively, these findings demonstrate that circCLASP1 promotes BC progression and an immunosuppressive microenvironment via the CCT2/GLI1/SNAIL axis, highlighting its potential as a prognostic biomarker and therapeutic target for BC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 49","pages":"4765-4780"},"PeriodicalIF":7.3,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541561","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}
Pub Date : 2025-11-17DOI: 10.1038/s41388-025-03622-7
Julia Reinhardt, Berno Dankbar, Fabienne Geers, Eugenie Werbenko, Christiane Geyer, Annalen Bleckmann, Kerstin Menck, Anne Grözinger, Wolfgang Hartmann, Joke Tio, Carsten Höltke, Anne Helfen, Andreas Lodberg, Rosa Al-Qasemi, Denise Beckmann, Sarah Bödecker, Simon Kleimann, Linda Wessendorf, Deniz Wawersig, Thomas Pap, Corinna Wehmeyer
Breast cancer (BC)-derived bone metastases colonize bone and drive severe bone degradation through complex interactions with bone-resorbing osteoclasts (OCs). Subsequent bone resorption liberates matrix-stored factors, such as TGF-β and calcium, which further stimulate tumor proliferation and exacerbate bone destruction. Myostatin (Mstn), a member of the TGF-β superfamily, is known to enhance OC differentiation and bone resorption in models of musculoskeletal disease; however, its role in BC-associated bone lesions and metastases remains unknown. Here, we demonstrate that bone metastases from BC patients express Mstn, predominantly localized at the osteoclast-rich bone–tumor interface. In vitro, both direct and indirect interactions between BC cells and OC precursors significantly increased OC formation and resorptive activity. Antibody-mediated blockade of Mstn attenuated these effects by inhibiting SMAD2 phosphorylation. In vivo, targeting Mstn in 4T1 and MDA-MB-231 murine models of BC-induced bone destruction resulted in elevated bone density, increased muscle mass, and reduced OC numbers compared to controls. Furthermore, anti-Mstn treatment decreased the burden of bone metastases in MDA-MB-231-bearing mice. Collectively, these findings identify Mstn as a previously unrecognized driver of BC-induced osteolysis and metastases, highlighting its potential as a therapeutic target in metastatic BC.
{"title":"Pharmacological inhibition of myostatin effectively ameliorates osteolytic lesions in syngeneic and xenograft breast cancer mouse models","authors":"Julia Reinhardt, Berno Dankbar, Fabienne Geers, Eugenie Werbenko, Christiane Geyer, Annalen Bleckmann, Kerstin Menck, Anne Grözinger, Wolfgang Hartmann, Joke Tio, Carsten Höltke, Anne Helfen, Andreas Lodberg, Rosa Al-Qasemi, Denise Beckmann, Sarah Bödecker, Simon Kleimann, Linda Wessendorf, Deniz Wawersig, Thomas Pap, Corinna Wehmeyer","doi":"10.1038/s41388-025-03622-7","DOIUrl":"10.1038/s41388-025-03622-7","url":null,"abstract":"Breast cancer (BC)-derived bone metastases colonize bone and drive severe bone degradation through complex interactions with bone-resorbing osteoclasts (OCs). Subsequent bone resorption liberates matrix-stored factors, such as TGF-β and calcium, which further stimulate tumor proliferation and exacerbate bone destruction. Myostatin (Mstn), a member of the TGF-β superfamily, is known to enhance OC differentiation and bone resorption in models of musculoskeletal disease; however, its role in BC-associated bone lesions and metastases remains unknown. Here, we demonstrate that bone metastases from BC patients express Mstn, predominantly localized at the osteoclast-rich bone–tumor interface. In vitro, both direct and indirect interactions between BC cells and OC precursors significantly increased OC formation and resorptive activity. Antibody-mediated blockade of Mstn attenuated these effects by inhibiting SMAD2 phosphorylation. In vivo, targeting Mstn in 4T1 and MDA-MB-231 murine models of BC-induced bone destruction resulted in elevated bone density, increased muscle mass, and reduced OC numbers compared to controls. Furthermore, anti-Mstn treatment decreased the burden of bone metastases in MDA-MB-231-bearing mice. Collectively, these findings identify Mstn as a previously unrecognized driver of BC-induced osteolysis and metastases, highlighting its potential as a therapeutic target in metastatic BC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 49","pages":"4781-4795"},"PeriodicalIF":7.3,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03622-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541603","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}
Pub Date : 2025-11-14DOI: 10.1038/s41388-025-03625-4
Wenbiao Chen, Chenhong Lin, Luolin Wang, Zhichao Yu, Yuxiuxiu Xu, Minhai Zhang, Lisheng Wang, Jun Yao
Hepatocellular carcinoma (HCC) is a common and serious type of malignant tumor with an unfavorable prognosis, partly attributed to the prevalence of hepatitis B virus (HBV) infection. However, the molecular mechanism underlying HBV-HCC are not yet fully understood. Here, we found that Kruppel-like factor 16 (KLF16) was significantly upregulated in HBV-HCC and KLF16 knockdown suppressed the growth and metastasis of HBV-infected HCC cells. Hepatitis B virus X protein (HBx)-mediated N6-methyladenosine (m6A) modification of KLF16 mRNA promoted the binding of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and IGF2BP3, thereby enhancing the stability of KLF16 mRNA. Furthermore, KLF16 was found to promote the transcription of chromosome 12 open reading frame 49 (C12orf49), which in turn increased programmed death-ligand 1 (PD-L1) expression by competitively binding to speckle-type POZ protein (SPOP) and blocking SPOP-mediated ubiquitination and degradation of PD-L1. HBx contributed to immune escape in HBV-HCC through the KLF16-C12orf49-PD-L1 axis. Importantly, inhibiting KLF16 significantly improved the efficacy of anti-PD-L1 therapy in HBV-HCC. Collectively, our study reveals the newly identified HBx-KLF16-C12orf49-PD-L1 axis and its role in promoting growth and immune evasion in HBV-HCC, offering a promising target for clinical interventions in HBV-HCC treatment.
{"title":"Hepatitis B virus X protein promotes the progression and immune escape of hepatocellular carcinoma by activating KLF16-C12orf49-PD-L1 axis","authors":"Wenbiao Chen, Chenhong Lin, Luolin Wang, Zhichao Yu, Yuxiuxiu Xu, Minhai Zhang, Lisheng Wang, Jun Yao","doi":"10.1038/s41388-025-03625-4","DOIUrl":"10.1038/s41388-025-03625-4","url":null,"abstract":"Hepatocellular carcinoma (HCC) is a common and serious type of malignant tumor with an unfavorable prognosis, partly attributed to the prevalence of hepatitis B virus (HBV) infection. However, the molecular mechanism underlying HBV-HCC are not yet fully understood. Here, we found that Kruppel-like factor 16 (KLF16) was significantly upregulated in HBV-HCC and KLF16 knockdown suppressed the growth and metastasis of HBV-infected HCC cells. Hepatitis B virus X protein (HBx)-mediated N6-methyladenosine (m6A) modification of KLF16 mRNA promoted the binding of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and IGF2BP3, thereby enhancing the stability of KLF16 mRNA. Furthermore, KLF16 was found to promote the transcription of chromosome 12 open reading frame 49 (C12orf49), which in turn increased programmed death-ligand 1 (PD-L1) expression by competitively binding to speckle-type POZ protein (SPOP) and blocking SPOP-mediated ubiquitination and degradation of PD-L1. HBx contributed to immune escape in HBV-HCC through the KLF16-C12orf49-PD-L1 axis. Importantly, inhibiting KLF16 significantly improved the efficacy of anti-PD-L1 therapy in HBV-HCC. Collectively, our study reveals the newly identified HBx-KLF16-C12orf49-PD-L1 axis and its role in promoting growth and immune evasion in HBV-HCC, offering a promising target for clinical interventions in HBV-HCC treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 48","pages":"4747-4762"},"PeriodicalIF":7.3,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524166","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}
Pub Date : 2025-11-13DOI: 10.1038/s41388-025-03619-2
Sha Chen, Li Xiang, Meng He, Qi Han, Yang Zhang, Mingzhen Yang, An Chen, Jiqin Lian, Shuhui Li
The reciprocal cross talk between breast cancer cells and the endothelial cells, through the secretion of growth factors, plays a vital role in angiogenesis and tumorigenesis. We previously demonstrated that chaperone-mediated autophagy (CMA) promotes breast cancer tumorigenesis. However, whether the cross talk between cancer cells with endothelial cells plays a role in CMA-mediated breast tumor tumorigenesis is unknown. We discovered that the conditioned medium (CM) from breast cancer cells with high CMA activity promoted tube formation of endothelial cells (ECs) via the VEGF-VEGFR2 axis. High CMA activity directly promoted angiogenesis of endothelial cells via the VEGF-VEGFR2 axis. The CM from ECs with high level CMA activity accelerated survival and migration of breast cancer cells in vitro via the VEGF-VEGFR2 axis. Co-injection of breast cancer cells mixed with ECs with high level CMA activity trigged angiogenesis and accelerated tumorigenesis in vivo. CMA activity and microvessel numbers were positively correlated with VEGF-VEGFR2 axis between paired breast tumor and normal adjacent tissue. CMA, a highly selective lysosome-dependent degradation process directly degrades VEGFR1 which can serve as a competitively regulatory factor for VEGFR2 regulating its signaling. Our study showed that the cross talk between breast cancer cells and endothelial cells induced by CMA -mediated degradation of VEGFR1 triggers angiogenesis and tumorigenesis via the VEGF-VEGFR2 axis.
{"title":"Chaperone-mediated autophagy controlling VEGFR1 degradation contributes cross talk between breast cancer cells and endothelial cells triggering tumorigenesis via the VEGF-VEGFR2 axis","authors":"Sha Chen, Li Xiang, Meng He, Qi Han, Yang Zhang, Mingzhen Yang, An Chen, Jiqin Lian, Shuhui Li","doi":"10.1038/s41388-025-03619-2","DOIUrl":"10.1038/s41388-025-03619-2","url":null,"abstract":"The reciprocal cross talk between breast cancer cells and the endothelial cells, through the secretion of growth factors, plays a vital role in angiogenesis and tumorigenesis. We previously demonstrated that chaperone-mediated autophagy (CMA) promotes breast cancer tumorigenesis. However, whether the cross talk between cancer cells with endothelial cells plays a role in CMA-mediated breast tumor tumorigenesis is unknown. We discovered that the conditioned medium (CM) from breast cancer cells with high CMA activity promoted tube formation of endothelial cells (ECs) via the VEGF-VEGFR2 axis. High CMA activity directly promoted angiogenesis of endothelial cells via the VEGF-VEGFR2 axis. The CM from ECs with high level CMA activity accelerated survival and migration of breast cancer cells in vitro via the VEGF-VEGFR2 axis. Co-injection of breast cancer cells mixed with ECs with high level CMA activity trigged angiogenesis and accelerated tumorigenesis in vivo. CMA activity and microvessel numbers were positively correlated with VEGF-VEGFR2 axis between paired breast tumor and normal adjacent tissue. CMA, a highly selective lysosome-dependent degradation process directly degrades VEGFR1 which can serve as a competitively regulatory factor for VEGFR2 regulating its signaling. Our study showed that the cross talk between breast cancer cells and endothelial cells induced by CMA -mediated degradation of VEGFR1 triggers angiogenesis and tumorigenesis via the VEGF-VEGFR2 axis.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 48","pages":"4727-4746"},"PeriodicalIF":7.3,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506123","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}
Pub Date : 2025-11-12DOI: 10.1038/s41388-025-03628-1
M. A. Westhoff, S. Zhou, M. G. Bachem, K. M. Debatin, S. Fulda
{"title":"Correction: Identification of a novel switch in the dominant forms of cell adhesion-mediated drug resistance in glioblastoma cells","authors":"M. A. Westhoff, S. Zhou, M. G. Bachem, K. M. Debatin, S. Fulda","doi":"10.1038/s41388-025-03628-1","DOIUrl":"10.1038/s41388-025-03628-1","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 48","pages":"4763-4764"},"PeriodicalIF":7.3,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03628-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506114","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}
Pub Date : 2025-11-08DOI: 10.1038/s41388-025-03617-4
Haley M. Hardin, Ethan W. Hass, Robert Allaway, Helen Morrison, Cristina Fernandez-Valle
NF2-related schwannomatosis (NF2-SWN) is a genetic predisposition to develop multiple schwannomas that cause serious neurological disabilities for which there are no approved drug therapies. We previously reported that the MEK inhibitor trametinib slowed schwannoma growth in two mouse models, however, ERK reactivation was observed. Pathway analysis of the proteome of trametinib-treated mouse schwannoma model cells predicted activation of BRD4. To elucidate the adaptive mechanisms contributing to cell survival, we studied the trametinib response in novel immortalized and non-immortalized human schwannoma model cells (MD-HSCs). MD-HSCs exposed to trametinib avoid cell death by upregulating expression of ECM and cell adhesion proteins resulting in an increase in cell size, stress fiber formation, and a switch from c-Jun to Krox20/Egr2 nuclear expression. We demonstrate that BET proteins mediate the survival response to trametinib in MD-HSCs. Preventing this epigenetic adaptation to trametinib with BET inhibitors induces schwannoma cell death. However, this response is not observed when BET inhibitors are combined with brigatinib, a multi-kinase inhibitor in clinical use. These findings highlight the complex cellular adaptations in schwannomas and suggest that targeting BET alongside MEK inhibition prevents resistance mechanisms and promotes cell death.
{"title":"BET proteins mediate survival mechanisms in human schwannoma model cells challenged with trametinib but not brigatinib","authors":"Haley M. Hardin, Ethan W. Hass, Robert Allaway, Helen Morrison, Cristina Fernandez-Valle","doi":"10.1038/s41388-025-03617-4","DOIUrl":"10.1038/s41388-025-03617-4","url":null,"abstract":"NF2-related schwannomatosis (NF2-SWN) is a genetic predisposition to develop multiple schwannomas that cause serious neurological disabilities for which there are no approved drug therapies. We previously reported that the MEK inhibitor trametinib slowed schwannoma growth in two mouse models, however, ERK reactivation was observed. Pathway analysis of the proteome of trametinib-treated mouse schwannoma model cells predicted activation of BRD4. To elucidate the adaptive mechanisms contributing to cell survival, we studied the trametinib response in novel immortalized and non-immortalized human schwannoma model cells (MD-HSCs). MD-HSCs exposed to trametinib avoid cell death by upregulating expression of ECM and cell adhesion proteins resulting in an increase in cell size, stress fiber formation, and a switch from c-Jun to Krox20/Egr2 nuclear expression. We demonstrate that BET proteins mediate the survival response to trametinib in MD-HSCs. Preventing this epigenetic adaptation to trametinib with BET inhibitors induces schwannoma cell death. However, this response is not observed when BET inhibitors are combined with brigatinib, a multi-kinase inhibitor in clinical use. These findings highlight the complex cellular adaptations in schwannomas and suggest that targeting BET alongside MEK inhibition prevents resistance mechanisms and promotes cell death.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 48","pages":"4699-4711"},"PeriodicalIF":7.3,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477087","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}
Pub Date : 2025-11-08DOI: 10.1038/s41388-025-03623-6
Younes Medkour, Catherine Rosa Dufour, Lingwei Han, Phillipe Hutton, Mirna Farhat, Anthony Alfonso, Amandine Rambur, Mathieu Vernier, Vincent Giguère
Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer that is associated with poor prognosis and a high risk of relapse, with limited treatment options. While the induction of senescence, a state of arrested cell growth, is generally achieved by available anticancer treatments, senescence can adversely promote tumorigenesis through an upheld augmented inflammatory state called senescence-associated secretory phenotype (SASP). Thus, the precise delineation of underlying regulatory mechanisms governing senescence is urgently needed. Herein, we investigated the beneficial anticancer senescence response elicited by silencing the expression of the promyelocytic leukemia protein (PML) in TNBC, where it exerts an oncogenic role. Functional genomics studies implicated the downregulation of a specific set of ribosomal protein (RP) genes tied to poor clinical outcome. Re-introduction of RPL38 or RPL39L alone, but not RPS14, a favorable outcome-associated RP, was sufficient to block the senescence phenotype induced by PML knockdown. RP gene regulation by PML was found to involve the assembly of a previously unrecognized PML-mTOR-RONIN transcriptional complex at their promoters. Furthermore, we show that RONIN levels are elevated in TNBC and that RONIN silencing can recapitulate the senescent phenotype of PML-deficient cells. This work offers new therapeutic insights for TNBC that involve senescence-inducing therapies or senolytics.
{"title":"Regulation of ribosomal gene expression and senescence by a PML-mTOR-RONIN nuclear complex in triple-negative breast cancer","authors":"Younes Medkour, Catherine Rosa Dufour, Lingwei Han, Phillipe Hutton, Mirna Farhat, Anthony Alfonso, Amandine Rambur, Mathieu Vernier, Vincent Giguère","doi":"10.1038/s41388-025-03623-6","DOIUrl":"10.1038/s41388-025-03623-6","url":null,"abstract":"Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer that is associated with poor prognosis and a high risk of relapse, with limited treatment options. While the induction of senescence, a state of arrested cell growth, is generally achieved by available anticancer treatments, senescence can adversely promote tumorigenesis through an upheld augmented inflammatory state called senescence-associated secretory phenotype (SASP). Thus, the precise delineation of underlying regulatory mechanisms governing senescence is urgently needed. Herein, we investigated the beneficial anticancer senescence response elicited by silencing the expression of the promyelocytic leukemia protein (PML) in TNBC, where it exerts an oncogenic role. Functional genomics studies implicated the downregulation of a specific set of ribosomal protein (RP) genes tied to poor clinical outcome. Re-introduction of RPL38 or RPL39L alone, but not RPS14, a favorable outcome-associated RP, was sufficient to block the senescence phenotype induced by PML knockdown. RP gene regulation by PML was found to involve the assembly of a previously unrecognized PML-mTOR-RONIN transcriptional complex at their promoters. Furthermore, we show that RONIN levels are elevated in TNBC and that RONIN silencing can recapitulate the senescent phenotype of PML-deficient cells. This work offers new therapeutic insights for TNBC that involve senescence-inducing therapies or senolytics.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 48","pages":"4712-4726"},"PeriodicalIF":7.3,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476634","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}
Pub Date : 2025-11-07DOI: 10.1038/s41388-025-03618-3
Lidwien P. Smabers, Hilde H. Nienhuis, Wendy W. J. de Leng, Paul Roepman, Ilcan Ö. A. Ciftcibasi, G. Emerens Wensink, Maarten A. Huismans, Liselot B. J. Valkenburg-van Iersel, Geert A. Cirkel, Elske C. Gootjes, Henk M. W. Verheul, Frank J. Jeurissen, Guus M. Bol, Onno Kranenburg, Miriam Koopman, Edwin Cuppen, Jeanine M. L. Roodhart
Whole genome sequencing (WGS) provides complete genetic information in one test, supporting the shift towards individualized metastatic colorectal cancer (mCRC) treatment. Although WGS is validated as a diagnostic test, the potential clinical implications for mCRC remain unknown. We evaluated the clinical consequences of WGS in 96 mCRC patients. Clinically actionable biomarkers were identified by a molecular biologist and medical oncologist, with added value defined as biomarkers undetected by standard diagnostics. We evaluated how these biomarkers informed treatment decisions. We used patient-derived organoids (PDOs) to test drug sensitivity to MET, MEK, and CDK4/6 inhibitors, translating genomic findings into functional evidence. WGS yields biomarkers with clinical implications in 81% of patients, with 49% (N = 47/96) identified by WGS that were not detected by guideline-based diagnostics, and 40% (N = 38/96) not detected by applied diagnostics. The proportion of patients receiving biomarker-based treatment has increased from 11% to at least 24% by WGS. PDOs with actionable biomarkers showed clear differential response to different biomarker-based treatments. WGS enables considerably more personalized therapeutic interventions and represents a promising approach in advancing precision oncology for mCRC patients. PDO pre-screening can refine therapy by identifying (in)effective treatments in a patient-specific context, to accelerate the development of personalized treatment.
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