Pub Date : 2026-01-04DOI: 10.1038/s41388-025-03671-y
Shengpan Wu, Baojun Wang, Hongzhao Li, Hanfeng Wang, Songliang Du, Xing Huang, Yang Fan, Yu Gao, Liangyou Gu, Qingbo Huang, Jianjun Chen, Xu Zhang, Yan Huang, Xin Ma
While Stimulator-of-interferon genes (STING) is an innate immune adapter crucial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study results revealed that STING depletion promoted infiltration of CD4+ and CD8+ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.
{"title":"Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma","authors":"Shengpan Wu, Baojun Wang, Hongzhao Li, Hanfeng Wang, Songliang Du, Xing Huang, Yang Fan, Yu Gao, Liangyou Gu, Qingbo Huang, Jianjun Chen, Xu Zhang, Yan Huang, Xin Ma","doi":"10.1038/s41388-025-03671-y","DOIUrl":"10.1038/s41388-025-03671-y","url":null,"abstract":"While Stimulator-of-interferon genes (STING) is an innate immune adapter crucial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study results revealed that STING depletion promoted infiltration of CD4+ and CD8+ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 5","pages":"620-635"},"PeriodicalIF":7.3,"publicationDate":"2026-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896709","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 : 2026-01-03DOI: 10.1038/s41388-025-03640-5
Marwa Taya, Daniel Fishman, Fahim Kanani, Lotem Zinger, Keren Merenbakh-Lamin, Shaked Elfasi Sosner, Anil Khushalrao Shendge, Anat Klein Goldberg, Uri Wolf, Galit Winkler, Eric Shifrut, Shmuel Cohen, Ido Wolf, Israel Sekler, Tami Rubinek
Activating mutations in the ligand-binding domain of the estrogen receptor (ER)-encoding (ESR1) gene are present in up to 40% of metastatic breast cancer (BC) patients and are strongly associated with a high risk of liver metastasis (LM) formation. Using the MCF-7 BC model, we investigated whether the increased hepatic tropism of ESR1-mutated BC cells is driven by their metabolic adaptation to the liver microenvironment. Indeed, metabolomic analysis revealed elevated metabolites related to the urea cycle (UC) in LM-forming ESR1-mutated cells compared to wild-type (WT) ER-expressing cells, which failed to generate LM. The subsequent proteomic, western blotting, and qPCR analyses demonstrated a dramatic upregulation of the UC constituent, the mitochondrial ornithine/citrulline transporter SLC25A15, in liver-predilected ESR1-mutated cells relative to their WT counterpart cells. Unlike WT cells, ESR1-mutated cells readily formed spheroids and exhibited enhanced migration in liver mimicking hepatocyte-conditioned media. In addition, we employed a novel ex vivo approach where ESR1 mutated cells were seeded onto colonized fresh liver tissue—which was abolished by SLC25A15 knockout. Moreover, SLC25A15 knockout robustly reduced the ability of ESR1-mutated cells to establish LM in vivo. These findings highlight SLC25A15-mediated dysregulation of the UC as a critical driver of BC hepatic metastasis and identify SLC25A15 as a potential therapeutic target for disrupting metastatic spread of BC to the liver.
{"title":"The role of the SLC25A15 transporter in the formation of liver metastasis in ESR1-mutated breast cancer","authors":"Marwa Taya, Daniel Fishman, Fahim Kanani, Lotem Zinger, Keren Merenbakh-Lamin, Shaked Elfasi Sosner, Anil Khushalrao Shendge, Anat Klein Goldberg, Uri Wolf, Galit Winkler, Eric Shifrut, Shmuel Cohen, Ido Wolf, Israel Sekler, Tami Rubinek","doi":"10.1038/s41388-025-03640-5","DOIUrl":"10.1038/s41388-025-03640-5","url":null,"abstract":"Activating mutations in the ligand-binding domain of the estrogen receptor (ER)-encoding (ESR1) gene are present in up to 40% of metastatic breast cancer (BC) patients and are strongly associated with a high risk of liver metastasis (LM) formation. Using the MCF-7 BC model, we investigated whether the increased hepatic tropism of ESR1-mutated BC cells is driven by their metabolic adaptation to the liver microenvironment. Indeed, metabolomic analysis revealed elevated metabolites related to the urea cycle (UC) in LM-forming ESR1-mutated cells compared to wild-type (WT) ER-expressing cells, which failed to generate LM. The subsequent proteomic, western blotting, and qPCR analyses demonstrated a dramatic upregulation of the UC constituent, the mitochondrial ornithine/citrulline transporter SLC25A15, in liver-predilected ESR1-mutated cells relative to their WT counterpart cells. Unlike WT cells, ESR1-mutated cells readily formed spheroids and exhibited enhanced migration in liver mimicking hepatocyte-conditioned media. In addition, we employed a novel ex vivo approach where ESR1 mutated cells were seeded onto colonized fresh liver tissue—which was abolished by SLC25A15 knockout. Moreover, SLC25A15 knockout robustly reduced the ability of ESR1-mutated cells to establish LM in vivo. These findings highlight SLC25A15-mediated dysregulation of the UC as a critical driver of BC hepatic metastasis and identify SLC25A15 as a potential therapeutic target for disrupting metastatic spread of BC to the liver.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 5","pages":"603-619"},"PeriodicalIF":7.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896755","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}
Indolent lung cancer is characterized by slow progression, and the patient may die of other causes before it becomes symptomatic. The increasing usage of lung cancer screening technologies has increased the detection of early-stage cancers, improved survival, and reduced mortality, but it also brings overdiagnosis or overtreatment for indolent lung cancer patients. In this study, we performed high-throughput whole-exome sequencing in lung adenocarcinoma (LUAD) patients with a tumor doubling time of more than 600 days (the indolent group) and another group with a tumor doubling time of less than 30 days (the aggressive group). We identified a novel germline variation in PDZRN4, rs74955204 (p.G121E, c.362 G > A) in the indolent group. The rs74955204 variant resulted in upregulated PDZRN4 expression and was positively correlated with the survival of LUAD patients. We confirmed that overexpression of PDZRN4 inhibits the ubiquitylation of HIF-1A mediated by TRIM28, thus activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, restricting lung cancer cell growth in vitro and in vivo. With the EGFRL858R-driven lung cancer mouse model as an example, we found that PDZRN4 knockout promoted, whereas PDZRN4 overexpression suppressed LUAD growth in vivo. In addition, recombinant PDZRN4 or screened small molecules retinoic acid showed potent inhibitory effects on EGFR-driven LUAD growth and amelioration of osimertinib resistance. Overall, our findings suggest that targeted PDZRN4 is a potential therapeutic strategy for treating LUAD. Examination of PDZRN4 rs74955204 variant may be an effective approach for the early detection of indolent lung cancer and to avoid overdiagnosis.
惰性肺癌的特点是进展缓慢，患者可能在出现症状之前死于其他原因。肺癌筛查技术的日益普及，增加了早期癌症的发现，提高了生存率，降低了死亡率，但也给惰性肺癌患者带来了过度诊断或过度治疗。在本研究中，我们对肿瘤加倍时间超过600天的肺腺癌（LUAD）患者（惰性组）和肿瘤加倍时间小于30天的肺腺癌（LUAD）患者（侵袭组）进行了高通量全外显子组测序。我们在惰性组中发现了PDZRN4， rs74955204 （p.G121E, c.362 G > a）的一种新的种系变异。rs74955204变异导致PDZRN4表达上调，与LUAD患者的生存呈正相关。我们在体外和体内证实，PDZRN4过表达可抑制TRIM28介导的HIF-1A泛素化，从而激活HIF-1A- igfbp3信号通路促进细胞凋亡，诱导NDRG1抑制EGFR-AKT信号通路，限制肺癌细胞生长。以egfrl858r驱动的肺癌小鼠模型为例，我们发现PDZRN4敲除促进体内LUAD的生长，而PDZRN4过表达抑制体内LUAD的生长。此外，重组PDZRN4或筛选的小分子维甲酸对egfr驱动的LUAD生长和改善奥西替尼耐药性有明显的抑制作用。总之，我们的研究结果表明，靶向PDZRN4是治疗LUAD的潜在治疗策略。检测PDZRN4 rs74955204变异可能是早期发现惰性肺癌，避免过度诊断的有效途径。摘要PDZRN4的种系变异rs74955204 （p.G121E, c.g 362 G > A）显著上调PDZRN4的表达，导致LUAD的惰性生长。过表达的PDZRN4可抑制TRIM28对HIF-1A的泛素化，激活HIF-1A- igfbp3信号通路促进细胞凋亡，诱导NDRG1抑制EGFR-AKT信号通路，从而限制肺癌细胞生长。
{"title":"PDZRN4 suppresses lung adenocarcinoma progression via inhibiting ubiquitin-mediated HIF-1A degradation","authors":"Honghao Li, Junfeng Wu, Hua Dai, Jiaming Li, Xiaoyan Bai, Yueli Sun, Jiaxin Lin, Yangsi Li, Peng Li, Lingchao Shi, Zhen Wang, Haiyan Tu, Ee Ke","doi":"10.1038/s41388-025-03670-z","DOIUrl":"10.1038/s41388-025-03670-z","url":null,"abstract":"Indolent lung cancer is characterized by slow progression, and the patient may die of other causes before it becomes symptomatic. The increasing usage of lung cancer screening technologies has increased the detection of early-stage cancers, improved survival, and reduced mortality, but it also brings overdiagnosis or overtreatment for indolent lung cancer patients. In this study, we performed high-throughput whole-exome sequencing in lung adenocarcinoma (LUAD) patients with a tumor doubling time of more than 600 days (the indolent group) and another group with a tumor doubling time of less than 30 days (the aggressive group). We identified a novel germline variation in PDZRN4, rs74955204 (p.G121E, c.362 G > A) in the indolent group. The rs74955204 variant resulted in upregulated PDZRN4 expression and was positively correlated with the survival of LUAD patients. We confirmed that overexpression of PDZRN4 inhibits the ubiquitylation of HIF-1A mediated by TRIM28, thus activating HIF-1A-IGFBP3 signaling to promote apoptosis, and inducing NDRG1 to inhibit EGFR-AKT signaling, restricting lung cancer cell growth in vitro and in vivo. With the EGFRL858R-driven lung cancer mouse model as an example, we found that PDZRN4 knockout promoted, whereas PDZRN4 overexpression suppressed LUAD growth in vivo. In addition, recombinant PDZRN4 or screened small molecules retinoic acid showed potent inhibitory effects on EGFR-driven LUAD growth and amelioration of osimertinib resistance. Overall, our findings suggest that targeted PDZRN4 is a potential therapeutic strategy for treating LUAD. Examination of PDZRN4 rs74955204 variant may be an effective approach for the early detection of indolent lung cancer and to avoid overdiagnosis.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"577-590"},"PeriodicalIF":7.3,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145857129","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 : 2025-12-27DOI: 10.1038/s41388-025-03661-0
Haoran Wang, Lichen Ge, Jianing Li, Ke Zhong, Shanzhi Li, Ningjing Ma, Lijun Tao, Jiawang Zhou, Zhaotong Wang, Xing Chang, Yunqing Lu, Yalan Rui, Guoyou Xie, Weifeng Yang, Zuanzong Xu, Abdulaziz Ahmed A. Saad, Xiansong Wang, Zhuojia Chen, Wanglin Li, Cheng Yi, Hongsheng Wang, Kun Zhang
RNA modification recognition proteins are crucial in cancer development and progression. Among all RNA modification-related proteins (RMRPs), Weighted Gene Co-expression Network Analysis (WGCNA), combined with comprehensive bioinformatic analysis, suggests that NAT10—the sole known writer of N4-acetylcytidine (ac4C)—is a critical regulatory protein in colorectal cancer (CRC) progression. NAT10 facilitates the malignancy phenotypes and DNA damage repair in CRC cells via its ac4C transferase activity and regulation of PPAN. Specifically, NAT10 enhances the translation efficiency of PPAN via acetylation at the C744 and C747 sites. In addition, NAT10 promotes the translation of ac4C-modified MYC mRNA. MYC protein then enhances PPAN transcription through binding to the PPAN promoter. The newly identified ac4C reader protein MYBBP1A mediates NAT10-induced translation of both PPAN and MYC. We further found that VDR binds to the NAT10 promoter to activate its transcription, resulting in the high expression of NAT10 in CRC. Xenograft studies and clinical data confirmed the role of the NAT10-PPAN axis in promoting CRC development and DNA damage repair. Collectively, our study reveals the role and underlying mechanism of mRNA ac4C modification in CRC progression, providing critical potential targets for CRC drug development.
{"title":"NAT10 triggers colorectal cancer progression via promoting PPAN-regulated DNA damage repair","authors":"Haoran Wang, Lichen Ge, Jianing Li, Ke Zhong, Shanzhi Li, Ningjing Ma, Lijun Tao, Jiawang Zhou, Zhaotong Wang, Xing Chang, Yunqing Lu, Yalan Rui, Guoyou Xie, Weifeng Yang, Zuanzong Xu, Abdulaziz Ahmed A. Saad, Xiansong Wang, Zhuojia Chen, Wanglin Li, Cheng Yi, Hongsheng Wang, Kun Zhang","doi":"10.1038/s41388-025-03661-0","DOIUrl":"10.1038/s41388-025-03661-0","url":null,"abstract":"RNA modification recognition proteins are crucial in cancer development and progression. Among all RNA modification-related proteins (RMRPs), Weighted Gene Co-expression Network Analysis (WGCNA), combined with comprehensive bioinformatic analysis, suggests that NAT10—the sole known writer of N4-acetylcytidine (ac4C)—is a critical regulatory protein in colorectal cancer (CRC) progression. NAT10 facilitates the malignancy phenotypes and DNA damage repair in CRC cells via its ac4C transferase activity and regulation of PPAN. Specifically, NAT10 enhances the translation efficiency of PPAN via acetylation at the C744 and C747 sites. In addition, NAT10 promotes the translation of ac4C-modified MYC mRNA. MYC protein then enhances PPAN transcription through binding to the PPAN promoter. The newly identified ac4C reader protein MYBBP1A mediates NAT10-induced translation of both PPAN and MYC. We further found that VDR binds to the NAT10 promoter to activate its transcription, resulting in the high expression of NAT10 in CRC. Xenograft studies and clinical data confirmed the role of the NAT10-PPAN axis in promoting CRC development and DNA damage repair. Collectively, our study reveals the role and underlying mechanism of mRNA ac4C modification in CRC progression, providing critical potential targets for CRC drug development.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"558-576"},"PeriodicalIF":7.3,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846820","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 : 2025-12-20DOI: 10.1038/s41388-025-03664-x
Yikang Wang, Chang Yuan, Zhichao Liu, Ning Ma, Cong Qi, Boyao Yu, Haizhen Jin, Chenyang Tian, Chunguang Li, Zhigang Li
Lymph node metastasis (LNM) is a major determinant of poor prognosis in esophageal squamous cell carcinoma (ESCC), with patients remaining at high risk of postoperative recurrence in the absence of reliable predictors or effective interventions. To address this unmet clinical need, we perform proteomic and bioinformatic analyses and identify lysosome-associated membrane protein 1 (LAMP1) as a critical driver of LNM in ESCC. LAMP1 is markedly overexpressed in primary tumors that with LNM and correlates with worse survival outcomes across independent cohorts. Gain- and loss-of-function experiments demonstrate that LAMP1 promotes lymphangiogenesis and lymphatic metastasis both in vitro and in vivo. Mechanistically, LAMP1 interacts with DNA-PKcs, mediates AKT activation, leading to VEGFC upregulation and secretion, thereby driving lymphangiogenesis and metastasis. Importantly, treatment with the LAMP1 inhibitor Parishin C significantly suppresses LNM in preclinical ESCC models. These findings uncover a previously unrecognized LAMP1/DNA-PKcs/AKT/VEGFC signaling axis that promotes ESCC progression and highlight LAMP1 as a promising biomarker and therapeutic target for preventing LNM and improving patient outcomes.
{"title":"LAMP1 enhances DNA-PKcs-mediated AKT phosphorylation and VEGFC secretion to promote lymph node metastasis in esophageal squamous cell carcinoma","authors":"Yikang Wang, Chang Yuan, Zhichao Liu, Ning Ma, Cong Qi, Boyao Yu, Haizhen Jin, Chenyang Tian, Chunguang Li, Zhigang Li","doi":"10.1038/s41388-025-03664-x","DOIUrl":"10.1038/s41388-025-03664-x","url":null,"abstract":"Lymph node metastasis (LNM) is a major determinant of poor prognosis in esophageal squamous cell carcinoma (ESCC), with patients remaining at high risk of postoperative recurrence in the absence of reliable predictors or effective interventions. To address this unmet clinical need, we perform proteomic and bioinformatic analyses and identify lysosome-associated membrane protein 1 (LAMP1) as a critical driver of LNM in ESCC. LAMP1 is markedly overexpressed in primary tumors that with LNM and correlates with worse survival outcomes across independent cohorts. Gain- and loss-of-function experiments demonstrate that LAMP1 promotes lymphangiogenesis and lymphatic metastasis both in vitro and in vivo. Mechanistically, LAMP1 interacts with DNA-PKcs, mediates AKT activation, leading to VEGFC upregulation and secretion, thereby driving lymphangiogenesis and metastasis. Importantly, treatment with the LAMP1 inhibitor Parishin C significantly suppresses LNM in preclinical ESCC models. These findings uncover a previously unrecognized LAMP1/DNA-PKcs/AKT/VEGFC signaling axis that promotes ESCC progression and highlight LAMP1 as a promising biomarker and therapeutic target for preventing LNM and improving patient outcomes.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"534-548"},"PeriodicalIF":7.3,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800090","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 : 2025-12-20DOI: 10.1038/s41388-025-03667-8
Charlotte Andrieu, Jojanneke Stoof, Dalal AlSultan, Laura Ivers, Jose Javier Berenguer Pina, Darko Skrobo, Jo Ballot, Debbie O’Reilly, Denis M. Collins, Alex J. Eustace, Cecily Quinn, Janice M. Walshe, Giuseppe Gullo, Naomi Walsh, John Crown
Metastatic breast cancer (MBC) is generally an incurable neoplasm. A small cohort of patients with HER2-positive MBC, however, achieve such prolonged remission without relapse following anti-HER2 therapy and chemotherapy, that it is speculated they might be cured. The genomes of these patients might provide insights into the underlying mechanisms for their successful treatment. Here, a total of 243 HER2-positive patients diagnosed with MBC between 2000 and 2015 were studied. Of these, 29 patients were identified as exceptional responders (ExR) with an overall survival (OS) > 60 months and no evidence of relapse, 54 patients with an OS > 60 months but who relapsed or developed progressive disease were defined as exceptional survivors (ExS), and 160 patients with an OS < 60 months were identified as short-term responders (STR). Whole-Genome Sequencing and centromere copy number (CCN) analysis was performed on 27 patients (12 ExR; 4 ExS; 11 STR). A significant amplification was observed in the centromeric regions of ExR, exhibiting higher CCN compared to the ExS and STR. Digital PCR validation of chromosome 4 centromere region D4Z1 copy number was not associated with ExR OS. Our results suggest that the amplification of centromere regions are associated with very prolonged remission and survival in patients with HER2-positive MBC.
{"title":"Chromosome centromere copy number amplification associated with exceptional response in HER2-positive metastatic breast cancer patients","authors":"Charlotte Andrieu, Jojanneke Stoof, Dalal AlSultan, Laura Ivers, Jose Javier Berenguer Pina, Darko Skrobo, Jo Ballot, Debbie O’Reilly, Denis M. Collins, Alex J. Eustace, Cecily Quinn, Janice M. Walshe, Giuseppe Gullo, Naomi Walsh, John Crown","doi":"10.1038/s41388-025-03667-8","DOIUrl":"10.1038/s41388-025-03667-8","url":null,"abstract":"Metastatic breast cancer (MBC) is generally an incurable neoplasm. A small cohort of patients with HER2-positive MBC, however, achieve such prolonged remission without relapse following anti-HER2 therapy and chemotherapy, that it is speculated they might be cured. The genomes of these patients might provide insights into the underlying mechanisms for their successful treatment. Here, a total of 243 HER2-positive patients diagnosed with MBC between 2000 and 2015 were studied. Of these, 29 patients were identified as exceptional responders (ExR) with an overall survival (OS) > 60 months and no evidence of relapse, 54 patients with an OS > 60 months but who relapsed or developed progressive disease were defined as exceptional survivors (ExS), and 160 patients with an OS < 60 months were identified as short-term responders (STR). Whole-Genome Sequencing and centromere copy number (CCN) analysis was performed on 27 patients (12 ExR; 4 ExS; 11 STR). A significant amplification was observed in the centromeric regions of ExR, exhibiting higher CCN compared to the ExS and STR. Digital PCR validation of chromosome 4 centromere region D4Z1 copy number was not associated with ExR OS. Our results suggest that the amplification of centromere regions are associated with very prolonged remission and survival in patients with HER2-positive MBC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"549-557"},"PeriodicalIF":7.3,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03667-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800087","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}
The USP37 gene encodes a deubiquitylase (DUB), which catalyzes the proteolytic removal of ubiquitin moieties from proteins to modulate their stability, cellular localization or activity. Its expression is downregulated in a subgroup of medulloblastomas driven by constitutive activation of sonic hedgehog (SHH) signaling. Patients with SHH-driven medulloblastomas with elevated expression of the RE1 silencing transcription factor (REST) and reduced expression of USP37 have poor outcomes. In previous studies, we showed sustained proliferation of SHH-medulloblastoma cells due to blockade of terminal cell cycle exit and neuronal differentiation stemming from a failure in USP37-dependent stabilization of its target, the cyclin-dependent kinase inhibitor (CDKI)-p27. This finding suggested a tumor suppressive function for USP37. Interestingly, the current study also uncovered Raptor, a component of the mTORC1 complex, as a novel target of USP37. Under conditions of low-USP37 expression, reduced Raptor stability and mTORC1 activity caused a decline in phosphorylation of 4E-binding protein 1 (4EBP1) and increased its interaction with eukaryotic elongation factor 4E (eIF4E), which is known to inhibit CAP-dependent translation initiation. Surprisingly, a subset of patients with SHH-driven medulloblastomas with elevated expression of USP37 and the Glioma-associated Oncogene 1 (GLI1), also exhibited poor outcomes. Using genetic and biochemical analyses, we showed that USP37-mediated stabilization of GLI1, a terminal effector of SHH signaling, increases pathway activity and upregulates expression of its target oncogene product, CCND1, to drive cell proliferation. These data indicate that USP37 elevation in SHH-driven medulloblastomas has the potential to promote non-canonical activation of SHH signaling. Overall, our findings suggest that USP37 may have context-specific oncogenic and tumor suppressive roles in medulloblastoma cells.
{"title":"Identification of Raptor and GLI1 as USP37 substrates highlight its context-specific function in medulloblastoma cells","authors":"Ashutosh Singh, Donghang Cheng, Amanda R. Haltom, Yanwen Yang, Tara Dobson, Rashieda Hatcher, Veena Rajaram, Vidya Gopalakrishnan","doi":"10.1038/s41388-025-03651-2","DOIUrl":"10.1038/s41388-025-03651-2","url":null,"abstract":"The USP37 gene encodes a deubiquitylase (DUB), which catalyzes the proteolytic removal of ubiquitin moieties from proteins to modulate their stability, cellular localization or activity. Its expression is downregulated in a subgroup of medulloblastomas driven by constitutive activation of sonic hedgehog (SHH) signaling. Patients with SHH-driven medulloblastomas with elevated expression of the RE1 silencing transcription factor (REST) and reduced expression of USP37 have poor outcomes. In previous studies, we showed sustained proliferation of SHH-medulloblastoma cells due to blockade of terminal cell cycle exit and neuronal differentiation stemming from a failure in USP37-dependent stabilization of its target, the cyclin-dependent kinase inhibitor (CDKI)-p27. This finding suggested a tumor suppressive function for USP37. Interestingly, the current study also uncovered Raptor, a component of the mTORC1 complex, as a novel target of USP37. Under conditions of low-USP37 expression, reduced Raptor stability and mTORC1 activity caused a decline in phosphorylation of 4E-binding protein 1 (4EBP1) and increased its interaction with eukaryotic elongation factor 4E (eIF4E), which is known to inhibit CAP-dependent translation initiation. Surprisingly, a subset of patients with SHH-driven medulloblastomas with elevated expression of USP37 and the Glioma-associated Oncogene 1 (GLI1), also exhibited poor outcomes. Using genetic and biochemical analyses, we showed that USP37-mediated stabilization of GLI1, a terminal effector of SHH signaling, increases pathway activity and upregulates expression of its target oncogene product, CCND1, to drive cell proliferation. These data indicate that USP37 elevation in SHH-driven medulloblastomas has the potential to promote non-canonical activation of SHH signaling. Overall, our findings suggest that USP37 may have context-specific oncogenic and tumor suppressive roles in medulloblastoma cells.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"521-533"},"PeriodicalIF":7.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03651-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775259","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}
Numerous ubiquitination-related proteases (URPs) have been identified as facilitators of disease progression through the disruption of ubiquitination homeostasis in substrate proteins. Notably, some URPs have exhibited non-classical biological functions. In this study, we experimentally elucidate the role of the E3 ubiquitin ligase IRF2BPL as transcriptional activator that promotes malignant phenotypes in esophageal squamous cell carcinoma (ESCC) and inhibits the infiltration of various immune cells within the tumor microenvironment. Specifically, we found that IRF2BPL is highly expressed in ESCC cells and promotes IGFBP2 transcription, thereby facilitating ESCC development both in vivo and in vitro. Moreover, the chemical drug ONC201 was shown to effectively impede ESCC progression induced by the hyperactive IRF2BPL-IGFBP2 axis in tumor cells. Collectively, our findings verified that the IRF2BPL-IGFBP2 axis plays a critical role in enhancing ESCC progression by increasing the malignancy of ESCC cells and fostering an immune-deficient tumor microenvironment. Targeting the IRF2BPL-IGFBP2 axis may represent a promising therapeutic strategy for ESCC.
{"title":"IRF2BPL transcriptionally regulates IGFBP2 to promote tumor progression and suppresses immune cell infiltration in esophageal squamous cell carcinoma","authors":"Yueguang Wu, Heyang Cui, Longlong Wang, Ning Ding, Yongjia Weng, Yikun Cheng, Shanshan Bi, Heng Xiao, Mingwei Gao, Huijuan Liu, Qiqin Song, Weimin Zhang, Yongping Cui","doi":"10.1038/s41388-025-03658-9","DOIUrl":"10.1038/s41388-025-03658-9","url":null,"abstract":"Numerous ubiquitination-related proteases (URPs) have been identified as facilitators of disease progression through the disruption of ubiquitination homeostasis in substrate proteins. Notably, some URPs have exhibited non-classical biological functions. In this study, we experimentally elucidate the role of the E3 ubiquitin ligase IRF2BPL as transcriptional activator that promotes malignant phenotypes in esophageal squamous cell carcinoma (ESCC) and inhibits the infiltration of various immune cells within the tumor microenvironment. Specifically, we found that IRF2BPL is highly expressed in ESCC cells and promotes IGFBP2 transcription, thereby facilitating ESCC development both in vivo and in vitro. Moreover, the chemical drug ONC201 was shown to effectively impede ESCC progression induced by the hyperactive IRF2BPL-IGFBP2 axis in tumor cells. Collectively, our findings verified that the IRF2BPL-IGFBP2 axis plays a critical role in enhancing ESCC progression by increasing the malignancy of ESCC cells and fostering an immune-deficient tumor microenvironment. Targeting the IRF2BPL-IGFBP2 axis may represent a promising therapeutic strategy for ESCC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"505-520"},"PeriodicalIF":7.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781331","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 : 2025-12-17DOI: 10.1038/s41388-025-03663-y
Feng Ji, Kai Yan, Bo Ding, Yuxin Zhu, Mengchen Rao, Kexing Gao, Hao Lin, Yiyang Shan, Sicong Liu, Zhongdang Xiao, Yang Shen
Ovarian cancer (OC) remains a lethal malignancy with limited treatment options owing to antigen heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, we designed a unique chimeric Antigen Receptor T-Cell (CAR-T) construct (B4M3) that integrates an anti-MSLN scFv linked to the CD3ζ activation domain and an anti-B7H3 scFv linked to the 4-1BB co-stimulatory domain. In vitro, B4M3 CAR-T cells exhibited robust cytotoxicity against OC cell lines with enhanced degranulation (CD107a) and efficient tumor cell killing, even at low effector-to-target ratios. In vivo, B4M3 CAR-T cells significantly inhibited tumor growth and prolonged survival and demonstrated superior tumor infiltration and persistence in OC xenograft models. Imaging mass cytometry (IMC) revealed that B4M3 treatment reshaped the TME, increased cytotoxic T lymphocyte (CTL) infiltration, and reduced regulatory T cells (Tregs). Mechanistically, B4M3 therapy upregulated TGF-β, promoting Th17 differentiation and CTL recruitment, thereby enhancing anti-tumor immunity. Our findings demonstrate that B4M3 CAR-T cells effectively address antigen heterogeneity and enhance therapeutic efficacy in OC, thereby offering a promising strategy for solid tumor immunotherapy.
{"title":"Dual-target CAR-T therapy for ovarian cancer: synergistic targeting of MSLN and B7H3 enhances anti-tumor efficacy and overcomes antigen heterogeneity","authors":"Feng Ji, Kai Yan, Bo Ding, Yuxin Zhu, Mengchen Rao, Kexing Gao, Hao Lin, Yiyang Shan, Sicong Liu, Zhongdang Xiao, Yang Shen","doi":"10.1038/s41388-025-03663-y","DOIUrl":"10.1038/s41388-025-03663-y","url":null,"abstract":"Ovarian cancer (OC) remains a lethal malignancy with limited treatment options owing to antigen heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, we designed a unique chimeric Antigen Receptor T-Cell (CAR-T) construct (B4M3) that integrates an anti-MSLN scFv linked to the CD3ζ activation domain and an anti-B7H3 scFv linked to the 4-1BB co-stimulatory domain. In vitro, B4M3 CAR-T cells exhibited robust cytotoxicity against OC cell lines with enhanced degranulation (CD107a) and efficient tumor cell killing, even at low effector-to-target ratios. In vivo, B4M3 CAR-T cells significantly inhibited tumor growth and prolonged survival and demonstrated superior tumor infiltration and persistence in OC xenograft models. Imaging mass cytometry (IMC) revealed that B4M3 treatment reshaped the TME, increased cytotoxic T lymphocyte (CTL) infiltration, and reduced regulatory T cells (Tregs). Mechanistically, B4M3 therapy upregulated TGF-β, promoting Th17 differentiation and CTL recruitment, thereby enhancing anti-tumor immunity. Our findings demonstrate that B4M3 CAR-T cells effectively address antigen heterogeneity and enhance therapeutic efficacy in OC, thereby offering a promising strategy for solid tumor immunotherapy.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 3","pages":"446-458"},"PeriodicalIF":7.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775209","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 : 2025-12-17DOI: 10.1038/s41388-025-03666-9
David R. Butcher, Christopher N. Parris, Scott J. Crichton, Fiona C. Dempsey, Hussein N. Al-Ali
The renin-angiotensin system is a key regulator of blood pressure homeostasis, with its primary effector, the angiotensin II type 1 receptor (AT1R), mediating vasoconstriction and processes fundamental to cancer progression, including proliferation, angiogenesis, and metastasis. Elevated AT1R expression is consistently linked to poor prognosis and therapeutic resistance across various malignancies. Preclinical studies provide compelling evidence that AT1R activation drives key cancer related processes, while its inhibition by angiotensin receptor blockers (ARBs) suppresses tumour growth, induces apoptosis, reduces angiogenesis, and inhibits metastasis across a wide range of cancer models. Critically, ARBs effectively modulate the tumour microenvironment (TME), alleviating fibrosis, promoting anti-tumour immune cell phenotypes, and enhancing the efficacy of targeted therapies, chemotherapies, and immunotherapies. Despite this strong preclinical evidence and supporting retrospective population studies, clinical translation of ARBs in oncology remains inconsistent, with trials often limited by design, patient heterogeneity, and supra-therapeutic ARB dosages required for acute anti-cancer effects. This review seeks to summarise the current understanding of AT1R’s role in cancer, highlight preclinical and clinical investigations of targeting RAS, and suggest further strategies to unlock its therapeutic potential. Realising the full therapeutic promise of AT1R targeting in oncology requires a multifaceted approach, including the development of innovative delivery systems, such as TME-activated ARBs, and the exploration of advanced therapeutic modalities, such as antibody based AT1R inhibitors. Rigorously designed clinical trials that include biomarker-driven patient stratification to identify responsive cohorts are crucial to define the context-dependent role of AT1R and conclusively establish its clinical utility as a combinatorial strategy to enhance patient outcomes.
{"title":"Unlocking the potential of targeting the angiotensin II type 1 receptor in cancer","authors":"David R. Butcher, Christopher N. Parris, Scott J. Crichton, Fiona C. Dempsey, Hussein N. Al-Ali","doi":"10.1038/s41388-025-03666-9","DOIUrl":"10.1038/s41388-025-03666-9","url":null,"abstract":"The renin-angiotensin system is a key regulator of blood pressure homeostasis, with its primary effector, the angiotensin II type 1 receptor (AT1R), mediating vasoconstriction and processes fundamental to cancer progression, including proliferation, angiogenesis, and metastasis. Elevated AT1R expression is consistently linked to poor prognosis and therapeutic resistance across various malignancies. Preclinical studies provide compelling evidence that AT1R activation drives key cancer related processes, while its inhibition by angiotensin receptor blockers (ARBs) suppresses tumour growth, induces apoptosis, reduces angiogenesis, and inhibits metastasis across a wide range of cancer models. Critically, ARBs effectively modulate the tumour microenvironment (TME), alleviating fibrosis, promoting anti-tumour immune cell phenotypes, and enhancing the efficacy of targeted therapies, chemotherapies, and immunotherapies. Despite this strong preclinical evidence and supporting retrospective population studies, clinical translation of ARBs in oncology remains inconsistent, with trials often limited by design, patient heterogeneity, and supra-therapeutic ARB dosages required for acute anti-cancer effects. This review seeks to summarise the current understanding of AT1R’s role in cancer, highlight preclinical and clinical investigations of targeting RAS, and suggest further strategies to unlock its therapeutic potential. Realising the full therapeutic promise of AT1R targeting in oncology requires a multifaceted approach, including the development of innovative delivery systems, such as TME-activated ARBs, and the exploration of advanced therapeutic modalities, such as antibody based AT1R inhibitors. Rigorously designed clinical trials that include biomarker-driven patient stratification to identify responsive cohorts are crucial to define the context-dependent role of AT1R and conclusively establish its clinical utility as a combinatorial strategy to enhance patient outcomes.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 4","pages":"479-490"},"PeriodicalIF":7.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03666-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775257","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：