Pub Date : 2025-11-24DOI: 10.1038/s41388-025-03631-6
Yongtao Li, Zhicheng Zhou, Yiqun Zhang, Deyong Jia, Ding Wang, Mary C. Reiger, Chad J. Creighton, Peter S. Nelson, Eva Corey, Colm Morrissey, Li Xin
Wnt signaling is a complex pathway consisting of numerous ligands and frizzled (FZD) receptors. These signaling components are widely expressed in human prostate tissues and often undergo upregulation or mutation in advanced prostate cancers. Enhanced Wnt signaling promotes prostate cancer cell proliferation, metastasis, and resistance to therapy. However, targeting pan-Wnt signaling poses challenges due to tissue toxicity. We show that FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced human prostate cancers. Knockdown of FZD6 suppresses both in vitro and in vivo growth of various prostate cancer cell lines and patient-derived xenograft models. FZD6 knockdown impairs DNA double-strand break (DSB) repair, as determined by both resolution of γH2AX foci and DNA DSB repair reporter assays. Mechanistically, FZD6 knockdown-induced growth suppression is linked to reduced activities of SRC kinase and STAT3, while DNA damage repair deficiency is mediated through WEE1 downregulation via PLK1. Knockdown of FZD6 enhances the therapeutic efficacy of genotoxic agents for prostate cancer cells. A kinome-wide CRISPR-Cas9 knockout screen reveals that FZD6 inhibition sensitizes prostate cancer cells to the inhibition of PKMYT1, a WEE kinase family member. Collectively, we demonstrate that targeting a single FZD receptor highly expressed in prostate cancers can yield significant therapeutic efficacy, and uncover therapeutic vulnerabilities associated with FZD6 inhibition.
{"title":"Targeting FZD6 creates therapeutically actionable vulnerabilities for advanced prostate cancer","authors":"Yongtao Li, Zhicheng Zhou, Yiqun Zhang, Deyong Jia, Ding Wang, Mary C. Reiger, Chad J. Creighton, Peter S. Nelson, Eva Corey, Colm Morrissey, Li Xin","doi":"10.1038/s41388-025-03631-6","DOIUrl":"10.1038/s41388-025-03631-6","url":null,"abstract":"Wnt signaling is a complex pathway consisting of numerous ligands and frizzled (FZD) receptors. These signaling components are widely expressed in human prostate tissues and often undergo upregulation or mutation in advanced prostate cancers. Enhanced Wnt signaling promotes prostate cancer cell proliferation, metastasis, and resistance to therapy. However, targeting pan-Wnt signaling poses challenges due to tissue toxicity. We show that FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced human prostate cancers. Knockdown of FZD6 suppresses both in vitro and in vivo growth of various prostate cancer cell lines and patient-derived xenograft models. FZD6 knockdown impairs DNA double-strand break (DSB) repair, as determined by both resolution of γH2AX foci and DNA DSB repair reporter assays. Mechanistically, FZD6 knockdown-induced growth suppression is linked to reduced activities of SRC kinase and STAT3, while DNA damage repair deficiency is mediated through WEE1 downregulation via PLK1. Knockdown of FZD6 enhances the therapeutic efficacy of genotoxic agents for prostate cancer cells. A kinome-wide CRISPR-Cas9 knockout screen reveals that FZD6 inhibition sensitizes prostate cancer cells to the inhibition of PKMYT1, a WEE kinase family member. Collectively, we demonstrate that targeting a single FZD receptor highly expressed in prostate cancers can yield significant therapeutic efficacy, and uncover therapeutic vulnerabilities associated with FZD6 inhibition.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4868-4877"},"PeriodicalIF":7.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03631-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595392","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 : 2025-11-24DOI: 10.1038/s41388-025-03646-z
Wei Ding, Zihan Ding, Qinghong Zeng, Yan Qiu, Christopher R. Donnelly, Yuqi Wu, Yuchen Jiang, Qi Han, Hao Xu, Hao Cui, Xiangfei Liu, Xin Chen, Sixin Jiang, Mei Huang, Dan Pan, Dan Yang, Li Li, Lihong Yao, Minghai Tang, Jing Li, Taiwen Li, Xiaoping Xu, Qianming Chen, Hang Zhao, Longyu Li, Lu Jiang, Xiaobo Luo
Early intervention of precancers is significant for improving cancer outcome. EZH2-mediated epigenetic modification was responsible for the immune escape of cancers; besides, tumor immune evasion is correlated with the impaired MHC-I antigen presentation machinery (APM). Oral potentially malignant disorders (OPMDs), represented by oral leukoplakia (OLK), usually precede head and neck squamous cell carcinoma (HNSCC). EZH2 is correlated with malignant transformation (MT) of OPMDs including OLK, while it remains undetermined that whether EZH2 mediates the initiation of HNSCC by repressing APM. Herein, EZH2 was first reported to negatively correlate with MHC-I and CD8+ GZMB+ T subsets which promote antitumor immunity in OPMDs. In vitro study uncovered that EZH2 triggers H3K27me3 on the promoters of MHC-I associated genes such as HLA-A/B/C, B2M and TAP1. Next, we constructed one hydrogel loaded with GSK126, a specific EZH2 inhibitor, denoted as PPT@GSK126 which is well-tolerated and highly adhesive to mucosa. Preclinical trials demonstrated that topical PPT@GSK126 could significantly prevent the MT of OPMDs and induce robust specific immune killing of dysplastic cells; while individual local αPD-1 therapy was unavailable, PPT@GSK126 synergized with topical αPD-1 therapy to significantly repress the cancerization of OPMDs. As EZH2 is highly expressed in numerous precancers, PPT@GSK126 has broad application prospects for reducing these tumor burdens.
{"title":"Prevention of cancer initiation by augmenting MHC-I antigen presentation via EZH2 inhibition","authors":"Wei Ding, Zihan Ding, Qinghong Zeng, Yan Qiu, Christopher R. Donnelly, Yuqi Wu, Yuchen Jiang, Qi Han, Hao Xu, Hao Cui, Xiangfei Liu, Xin Chen, Sixin Jiang, Mei Huang, Dan Pan, Dan Yang, Li Li, Lihong Yao, Minghai Tang, Jing Li, Taiwen Li, Xiaoping Xu, Qianming Chen, Hang Zhao, Longyu Li, Lu Jiang, Xiaobo Luo","doi":"10.1038/s41388-025-03646-z","DOIUrl":"10.1038/s41388-025-03646-z","url":null,"abstract":"Early intervention of precancers is significant for improving cancer outcome. EZH2-mediated epigenetic modification was responsible for the immune escape of cancers; besides, tumor immune evasion is correlated with the impaired MHC-I antigen presentation machinery (APM). Oral potentially malignant disorders (OPMDs), represented by oral leukoplakia (OLK), usually precede head and neck squamous cell carcinoma (HNSCC). EZH2 is correlated with malignant transformation (MT) of OPMDs including OLK, while it remains undetermined that whether EZH2 mediates the initiation of HNSCC by repressing APM. Herein, EZH2 was first reported to negatively correlate with MHC-I and CD8+ GZMB+ T subsets which promote antitumor immunity in OPMDs. In vitro study uncovered that EZH2 triggers H3K27me3 on the promoters of MHC-I associated genes such as HLA-A/B/C, B2M and TAP1. Next, we constructed one hydrogel loaded with GSK126, a specific EZH2 inhibitor, denoted as PPT@GSK126 which is well-tolerated and highly adhesive to mucosa. Preclinical trials demonstrated that topical PPT@GSK126 could significantly prevent the MT of OPMDs and induce robust specific immune killing of dysplastic cells; while individual local αPD-1 therapy was unavailable, PPT@GSK126 synergized with topical αPD-1 therapy to significantly repress the cancerization of OPMDs. As EZH2 is highly expressed in numerous precancers, PPT@GSK126 has broad application prospects for reducing these tumor burdens.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4878-4894"},"PeriodicalIF":7.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595395","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 : 2025-11-24DOI: 10.1038/s41388-025-03648-x
Justin Stebbing, George Miller
{"title":"Ten years of oncogene editorship: a decade of transformation","authors":"Justin Stebbing, George Miller","doi":"10.1038/s41388-025-03648-x","DOIUrl":"10.1038/s41388-025-03648-x","url":null,"abstract":"","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4833-4834"},"PeriodicalIF":7.3,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03648-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145595391","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}
Damage-associated molecular patterns (DAMPs) are secreted from damaged or dying cells and activate innate immune signaling via pattern-recognition receptors such as Toll-like receptors and cGAS. We previously showed that topotecan, a chemotherapeutic drug and topoisomerase I (TOP1) inhibitor, binds to ribosomal protein RPL15 and induces the secretion of DAMPs from cancer cells, which activate cGAS-STING signaling in dendritic cells. RPL15-knockdown B16-F10 melanoma tumors were sensitized to anti-PD-1 antibody, suggesting that RPL15 inhibition may have the potential to improve immune checkpoint inhibitor efficacy. However, topotecan and its derivatives, including SN-38, are highly cytotoxic because of their TOP1 inhibitory activity. Here, we synthesized SN-38-conjugated pomalidomide (SN38-PROTAC) and showed that SN38-PROTAC induced ubiquitin-mediated degradation of RPL15, but not TOP1. SN38-PROTAC treatment induced DAMP secretion from cancer cells, which activated cGAS-STING signaling in dendritic cells. The cytotoxicity of SN38-PROTAC in MCF7 cells was 100-fold lower than SN-38. SN38-PROTAC treatment increased the CTL/Treg ratio in tumors and sensitized B16-F10 tumors to anti-PD-1 antibody in a mouse model. The enhanced antitumor effects of SN38-PROTAC and anti-PD-1 antibody combination were abolished in STING-deficient mice. Our results indicate that SN38-PROTAC, which induces RPL15 degradation, has the potential to enhance ICI efficacy in PD-1-resistant cancer with low cytotoxicity.
{"title":"A selective RPL15 PROTAC degrader enhances anti-PD-1 immunotherapy in a murine melanoma tumor model","authors":"Runa Takahashi, Kazuki Yamamoto, Hikaru Toya, Haruka Shoji, Kohei Kawanishi, Kyoka Momosaki, Miyuki Yabe, Ken Takashima, Ryuta Muromoto, Satoshi Ichikawa, Tadashi Matsuda, Yuichi Kitai","doi":"10.1038/s41388-025-03641-4","DOIUrl":"10.1038/s41388-025-03641-4","url":null,"abstract":"Damage-associated molecular patterns (DAMPs) are secreted from damaged or dying cells and activate innate immune signaling via pattern-recognition receptors such as Toll-like receptors and cGAS. We previously showed that topotecan, a chemotherapeutic drug and topoisomerase I (TOP1) inhibitor, binds to ribosomal protein RPL15 and induces the secretion of DAMPs from cancer cells, which activate cGAS-STING signaling in dendritic cells. RPL15-knockdown B16-F10 melanoma tumors were sensitized to anti-PD-1 antibody, suggesting that RPL15 inhibition may have the potential to improve immune checkpoint inhibitor efficacy. However, topotecan and its derivatives, including SN-38, are highly cytotoxic because of their TOP1 inhibitory activity. Here, we synthesized SN-38-conjugated pomalidomide (SN38-PROTAC) and showed that SN38-PROTAC induced ubiquitin-mediated degradation of RPL15, but not TOP1. SN38-PROTAC treatment induced DAMP secretion from cancer cells, which activated cGAS-STING signaling in dendritic cells. The cytotoxicity of SN38-PROTAC in MCF7 cells was 100-fold lower than SN-38. SN38-PROTAC treatment increased the CTL/Treg ratio in tumors and sensitized B16-F10 tumors to anti-PD-1 antibody in a mouse model. The enhanced antitumor effects of SN38-PROTAC and anti-PD-1 antibody combination were abolished in STING-deficient mice. Our results indicate that SN38-PROTAC, which induces RPL15 degradation, has the potential to enhance ICI efficacy in PD-1-resistant cancer with low cytotoxicity.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4846-4854"},"PeriodicalIF":7.3,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03641-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588400","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 : 2025-11-22DOI: 10.1038/s41388-025-03600-z
Prerna R. Nepali, Edgar Gonzalez-Kozlova, Maitri Anegondi, Navneet Dogra, Maddison Archer, Goutam Chakraborty, Ashutosh K. Tewari, Benjamin D. Hopkins, Natasha Kyprianou
Epithelial mesenchymal transition (EMT) circumvents anoikis (cell death upon detachment from extracellular matrix) to promote prostate metastasis and therapy resistance. In this study, we investigated how TGF-β regulated EMT-MET (mesenchymal epithelial transition) phenotypic interconversions to enhance anoikis response in pre-clinical models of prostate cancer (PCa). We used human PCa cell line models: VCaP (androgen-sensitive, TGF-β responsive); 22RV1 (castration resistant prostate cancer); LNCaP; LNCaPTβRII (LNCaP cells overexpressing TGF-β receptor II, androgen-sensitive, TGF-β responsive); C4-2B parental and C4-2B TaxR (TGF-β unresponsive, taxane resistant). We assessed their response to TGF-β (EMT inducer) and two antitumor agents (DZ-50 and cabazitaxel (CBZ)) to understand the effect of EMT priming on anoikis vulnerability. Our findings demonstrate: (1) TGF-β induces EMT in LNCaPTβRII and apoptosis in VCaP. (2) LNCaPTβRII cells are primed by EMT to anoikis (downregulation of pSRC and cofilin). (3) Metabolic changes occur at EMT-anoikis intersection in LNCaPTβRII. (4) DZ-50 overcomes CBZ resistance in C4-2B TaxR and improves response in cells and castration-resistant organoids. These studies indicate that prostate cancer cells “programmed” to undergo phenotypic EMT become vulnerable to cell death via anoikis. Exploitation of this intersection is of potential significance in overcoming resistance to taxane chemotherapy in lethal prostate cancer.
{"title":"Effect of TGF-β mediated phenotypic changes on prostate cancer cell anoikis response","authors":"Prerna R. Nepali, Edgar Gonzalez-Kozlova, Maitri Anegondi, Navneet Dogra, Maddison Archer, Goutam Chakraborty, Ashutosh K. Tewari, Benjamin D. Hopkins, Natasha Kyprianou","doi":"10.1038/s41388-025-03600-z","DOIUrl":"10.1038/s41388-025-03600-z","url":null,"abstract":"Epithelial mesenchymal transition (EMT) circumvents anoikis (cell death upon detachment from extracellular matrix) to promote prostate metastasis and therapy resistance. In this study, we investigated how TGF-β regulated EMT-MET (mesenchymal epithelial transition) phenotypic interconversions to enhance anoikis response in pre-clinical models of prostate cancer (PCa). We used human PCa cell line models: VCaP (androgen-sensitive, TGF-β responsive); 22RV1 (castration resistant prostate cancer); LNCaP; LNCaPTβRII (LNCaP cells overexpressing TGF-β receptor II, androgen-sensitive, TGF-β responsive); C4-2B parental and C4-2B TaxR (TGF-β unresponsive, taxane resistant). We assessed their response to TGF-β (EMT inducer) and two antitumor agents (DZ-50 and cabazitaxel (CBZ)) to understand the effect of EMT priming on anoikis vulnerability. Our findings demonstrate: (1) TGF-β induces EMT in LNCaPTβRII and apoptosis in VCaP. (2) LNCaPTβRII cells are primed by EMT to anoikis (downregulation of pSRC and cofilin). (3) Metabolic changes occur at EMT-anoikis intersection in LNCaPTβRII. (4) DZ-50 overcomes CBZ resistance in C4-2B TaxR and improves response in cells and castration-resistant organoids. These studies indicate that prostate cancer cells “programmed” to undergo phenotypic EMT become vulnerable to cell death via anoikis. Exploitation of this intersection is of potential significance in overcoming resistance to taxane chemotherapy in lethal prostate cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 50","pages":"4835-4845"},"PeriodicalIF":7.3,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-025-03600-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582285","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 : 2025-11-20DOI: 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}
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