Pub Date : 2025-08-28DOI: 10.1038/s43018-025-01005-1
Daniel Delitto, Michael T. Longaker
Cancer-associated fibroblasts represent a functionally diverse and heterogeneous entity within the solid tumor microenvironment. Mitochondrial transfer from cancer cells to fibroblasts is now shown to act as a reprogramming stimulus, driving metabolic and functional differentiation of fibroblasts to support tumor growth.
{"title":"Cancer-derived mitochondria fuel fibroblasts to become pro-tumorigenic","authors":"Daniel Delitto, Michael T. Longaker","doi":"10.1038/s43018-025-01005-1","DOIUrl":"10.1038/s43018-025-01005-1","url":null,"abstract":"Cancer-associated fibroblasts represent a functionally diverse and heterogeneous entity within the solid tumor microenvironment. Mitochondrial transfer from cancer cells to fibroblasts is now shown to act as a reprogramming stimulus, driving metabolic and functional differentiation of fibroblasts to support tumor growth.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1615-1616"},"PeriodicalIF":28.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961843","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 : 2025-08-28DOI: 10.1038/s43018-025-01038-6
Michael Cangkrama, Huan Liu, Xiaoyu Wu, Josephine Yates, James Whipman, Christoph G. Gäbelein, Mai Matsushita, Luca Ferrarese, Sibilla Sander, Francesc Castro-Giner, Simran Asawa, Magdalena K. Sznurkowska, Manfred Kopf, Jörn Dengjel, Valentina Boeva, Nicola Aceto, Julia A. Vorholt, Sabine Werner
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies. Cangkrama et al. show that tumor cells from various cancer types use the mitochondrial trafficking protein MIRO2 and nanotubes to transfer mitochondria into surrounding fibroblasts, thereby inducing cancer-associated fibroblast differentiation and subsequent tumor growth.
{"title":"MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation","authors":"Michael Cangkrama, Huan Liu, Xiaoyu Wu, Josephine Yates, James Whipman, Christoph G. Gäbelein, Mai Matsushita, Luca Ferrarese, Sibilla Sander, Francesc Castro-Giner, Simran Asawa, Magdalena K. Sznurkowska, Manfred Kopf, Jörn Dengjel, Valentina Boeva, Nicola Aceto, Julia A. Vorholt, Sabine Werner","doi":"10.1038/s43018-025-01038-6","DOIUrl":"10.1038/s43018-025-01038-6","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies. Cangkrama et al. show that tumor cells from various cancer types use the mitochondrial trafficking protein MIRO2 and nanotubes to transfer mitochondria into surrounding fibroblasts, thereby inducing cancer-associated fibroblast differentiation and subsequent tumor growth.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1714-1733"},"PeriodicalIF":28.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01038-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961865","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 : 2025-08-27DOI: 10.1038/s43018-025-01024-y
Ronald A. DePinho
Ron DePinho received his MD from the Albert Einstein College of Medicine and completed his medical and postdoctoral training at Columbia University. He was the founding director of the Belfer Center at the Dana-Farber Cancer Institute. As president of the University of Texas MD Anderson Cancer Center, he launched the Cancer Moonshot initiative. He currently serves as a professor of cancer biology at the MD Anderson Cancer Center and was elected to the National Academies of Sciences and Medicine. He is the co-founder of several biotech companies and an advocate for innovation-driven healthspan solutions for the underserved.
Ron DePinho在爱因斯坦医学院获得医学博士学位，并在哥伦比亚大学完成了医学和博士后培训。他是丹娜-法伯癌症研究所贝尔弗中心的创始主任。作为德克萨斯大学MD安德森癌症中心的主席，他发起了癌症登月计划。他目前担任MD安德森癌症中心的癌症生物学教授，并当选为美国国家科学院和医学院院士。他是几家生物技术公司的联合创始人，并倡导为服务不足的人群提供创新驱动的健康解决方案。
{"title":"Telescopes, telomeres and turning points","authors":"Ronald A. DePinho","doi":"10.1038/s43018-025-01024-y","DOIUrl":"10.1038/s43018-025-01024-y","url":null,"abstract":"Ron DePinho received his MD from the Albert Einstein College of Medicine and completed his medical and postdoctoral training at Columbia University. He was the founding director of the Belfer Center at the Dana-Farber Cancer Institute. As president of the University of Texas MD Anderson Cancer Center, he launched the Cancer Moonshot initiative. He currently serves as a professor of cancer biology at the MD Anderson Cancer Center and was elected to the National Academies of Sciences and Medicine. He is the co-founder of several biotech companies and an advocate for innovation-driven healthspan solutions for the underserved.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 9","pages":"1479-1479"},"PeriodicalIF":28.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961813","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}
The tumor microenvironment evolves during tumor development and influences the cells in the microenvironment to orchestrate a supportive environment for tumor growth. Here we collected 4,483,367 cells across 36 cancer types and constructed a pan-cancer resource named TabulaTIME. Our integrated analyses reveal that CTHRC1 is a hallmark of extracellular matrix-related cancer-associated fibroblasts (CAFs) that are enriched in different cancer types. Spatiotemporal analyses further indicated that CTHRC1+ CAFs are located at the leading edge between the malignant and normal regions, potentially preventing immune infiltration. Moreover, we identified that SLPI+ macrophages exhibit profibrotic-associated phenotypes and colocalize with CTHRC1+ CAFs to form unique spatial ecotypes. Finally, we demonstrated that TabulaTIME can be used to analyze tumor ecotype composition and can serve as a reference for cell-type annotation. This work establishes a comprehensive single-cell landscape of the heterogenous TME and offers a potential therapeutic strategy for targeting the profibrotic ecotype in cancer treatment. Han et al. present TabulaTIME, a multicancer scRNA-seq resource, and report enrichment of extracellular matrix-related CTHRC1+ cancer-associated fibroblasts in proximity to SLPI+ macrophages, creating a profibrotic ecotype associated with tumor immunity.
{"title":"Spatiotemporal analyses of the pan-cancer single-cell landscape reveal widespread profibrotic ecotypes associated with tumor immunity","authors":"Ya Han, Lele Zhang, Dongqing Sun, Guangxu Cao, Yuting Wang, Jiali Yue, Junjie Hu, Zhonghua Dong, Fang Li, Taiwen Li, Peng Zhang, Qiu Wu, Chenfei Wang","doi":"10.1038/s43018-025-01039-5","DOIUrl":"10.1038/s43018-025-01039-5","url":null,"abstract":"The tumor microenvironment evolves during tumor development and influences the cells in the microenvironment to orchestrate a supportive environment for tumor growth. Here we collected 4,483,367 cells across 36 cancer types and constructed a pan-cancer resource named TabulaTIME. Our integrated analyses reveal that CTHRC1 is a hallmark of extracellular matrix-related cancer-associated fibroblasts (CAFs) that are enriched in different cancer types. Spatiotemporal analyses further indicated that CTHRC1+ CAFs are located at the leading edge between the malignant and normal regions, potentially preventing immune infiltration. Moreover, we identified that SLPI+ macrophages exhibit profibrotic-associated phenotypes and colocalize with CTHRC1+ CAFs to form unique spatial ecotypes. Finally, we demonstrated that TabulaTIME can be used to analyze tumor ecotype composition and can serve as a reference for cell-type annotation. This work establishes a comprehensive single-cell landscape of the heterogenous TME and offers a potential therapeutic strategy for targeting the profibrotic ecotype in cancer treatment. Han et al. present TabulaTIME, a multicancer scRNA-seq resource, and report enrichment of extracellular matrix-related CTHRC1+ cancer-associated fibroblasts in proximity to SLPI+ macrophages, creating a profibrotic ecotype associated with tumor immunity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1880-1898"},"PeriodicalIF":28.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01039-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961818","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}
Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation. A polygenic risk score (PRS) based on functional CRE variants effectively predicted CRC and precancerous lesions among 476,770 individuals. Notably, the functional variant rs10871066 was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, P = 1.03 × 10−13). Mechanistically, rs10871066 triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating KLF5 to activate oncogenic pathways and PIBF1 to suppress natural killer cell cytotoxicity. Our study provides a comprehensive resource of dynamic epigenomic atlas, a functionally informed PRS for risk prediction and insights into epigenetic mechanisms underlying CRC development. Lu et al. characterize cis-regulatory element dynamics at different stages of colorectal cancer progression and identify a functional variant associated with increased colorectal cancer risk because of selective transcription factor binding.
{"title":"Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings","authors":"Zequn Lu, Can Chen, Heng Zhang, Bin Li, Yizhuo Liu, Jiayi Guo, Runying Xu, Ke Shi, Qianying Ma, Ming Zhang, Yimin Cai, Jinyu Huang, Hui Geng, Linyun Fan, Caibo Ning, Yanmin Li, Shuoni Chen, Wen Tian, Kexin Hu, Haijie Li, Xiaojun Yang, Chaoqun Huang, Yongchang Wei, Xu Zhu, Xiangpan Li, Zhen Xiong, Ming Cai, Xiaoyang Wang, Shaokai Zhang, Hongda Chen, Min Dai, Kun Chen, Mingjuan Jin, Meng Jin, Ying Zhu, Jianbo Tian, Xiaoping Miao","doi":"10.1038/s43018-025-01031-z","DOIUrl":"10.1038/s43018-025-01031-z","url":null,"abstract":"Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation. A polygenic risk score (PRS) based on functional CRE variants effectively predicted CRC and precancerous lesions among 476,770 individuals. Notably, the functional variant rs10871066 was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, P = 1.03 × 10−13). Mechanistically, rs10871066 triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating KLF5 to activate oncogenic pathways and PIBF1 to suppress natural killer cell cytotoxicity. Our study provides a comprehensive resource of dynamic epigenomic atlas, a functionally informed PRS for risk prediction and insights into epigenetic mechanisms underlying CRC development. Lu et al. characterize cis-regulatory element dynamics at different stages of colorectal cancer progression and identify a functional variant associated with increased colorectal cancer risk because of selective transcription factor binding.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1777-1799"},"PeriodicalIF":28.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961855","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}
The bidirectional interaction between the brain and peripheral tumors is critical but poorly understood. Here we show GABAergic neurons in the lateral septum, a key brain region implicated in emotional regulation, connect via a polysynaptic circuit to enteric cholinergic neurons that send nerve fibers into the tumor microenvironment, which were then hijacked by colorectal cancer cells to sustain tumor growth in mice. Functionally, activation of this septo-enteric circuit induces GABA release from enteric cholinergic neurons, which in turn activates epsilon-subunit-containing GABAA receptors on tumor cells. Notably, chronic restraint stress potentiates activity within this circuit, exacerbating tumor progression. Clinically, patients with colorectal cancer exhibiting elevated neuronal activity in the septal region present with larger primary tumors. Collectively, our findings uncover a stress-sensitive septo-enteric polysynaptic pathway exploited by cancer cells to promote tumor growth, underscoring the previously unrecognized role of lateral septum-mediated neural circuitry and psychological stress in cancer progression. Li and colleagues report that a septo-enteric polysynaptic circuit that is activated by chronic stress links the brain to the tumor microenvironment to promote colorectal cancer growth.
{"title":"Colorectal cancer cells hijack a brain–gut polysynaptic circuit from the lateral septum to enteric neurons to sustain tumor growth","authors":"Ying Li, Hao Yu, Zi-Ming Li, Kai-Wen Yin, Shi-Yang Jin, Chao-Chao Chen, Ming-Shi Tan, Chuan-Jie Zhang, Xun-Hua Liu, Wei-Peng Li, Jian-Ming Yang, Ai-Jun Zhou, Xiang Zhang, En-De Ni, Meng-Ling Wang, Hui Mo, Chao Qin, Jian Hu, Shu-Ji Li, Tian-Ming Gao, Jian-Ming Li","doi":"10.1038/s43018-025-01033-x","DOIUrl":"10.1038/s43018-025-01033-x","url":null,"abstract":"The bidirectional interaction between the brain and peripheral tumors is critical but poorly understood. Here we show GABAergic neurons in the lateral septum, a key brain region implicated in emotional regulation, connect via a polysynaptic circuit to enteric cholinergic neurons that send nerve fibers into the tumor microenvironment, which were then hijacked by colorectal cancer cells to sustain tumor growth in mice. Functionally, activation of this septo-enteric circuit induces GABA release from enteric cholinergic neurons, which in turn activates epsilon-subunit-containing GABAA receptors on tumor cells. Notably, chronic restraint stress potentiates activity within this circuit, exacerbating tumor progression. Clinically, patients with colorectal cancer exhibiting elevated neuronal activity in the septal region present with larger primary tumors. Collectively, our findings uncover a stress-sensitive septo-enteric polysynaptic pathway exploited by cancer cells to promote tumor growth, underscoring the previously unrecognized role of lateral septum-mediated neural circuitry and psychological stress in cancer progression. Li and colleagues report that a septo-enteric polysynaptic circuit that is activated by chronic stress links the brain to the tumor microenvironment to promote colorectal cancer growth.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1800-1820"},"PeriodicalIF":28.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961905","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 : 2025-08-21DOI: 10.1038/s43018-025-01029-7
Zhiren Wang, Wenpan Li, Yanhao Jiang, Teng Ma, Mengwen Li, Shuang Wu, Tuyen Ba Tran, Leyla Estrella Cordova, Ethan Lin, Aaron James Scott, Jennifer Erdrich, Joyce Schroeder, Pavani Chalasani, Jianqin Lu
Taxol and Abraxane, the US Food and Drug Administration-approved paclitaxel (PTX) formulations, have revealed hypersensitivity due to excipients and mediocre efficacy due to insufficient tumor penetration, respectively. Here we developed a sphingolipid-derived PTX nanovesicle (paclitaxome) via covalently conjugating PTX to sphingomyelin, which improved pharmacokinetics and enhanced efficacy in metastatic triple-negative breast cancer and pancreatic cancer female mice and reduced myelosuppression. To bolster tumor penetration and reduce phagocytosis, we engineered a cationization-enabled transcytosis machinery by installing an ultra-pH-sensitive azepane (AZE) probe into paclitaxome and masked nanovesicle surface with a CD47 ‘self’ peptide (CD47p). The resulting CD47p/AZE–paclitaxome synchronized the co-delivery of gemcitabine or carboplatin to boost tumor inhibition and eradicate metastasis in late-stage KPC-Luc pancreatic cancer model and prevent tumor relapse and extend survival in postsurgical 4T1-Luc2 triple-negative breast cancer model in female mice. CD47p/AZE–paclitaxome also outperformed previous promising PTX nanoformulations. Finally, the series of nanoparticle modifications was applied to camptothecin, demonstrating its generalizability. Wang et al. designed sphingomyelin-derived vesicles that deliver paclitaxel to tumor site, improving its therapeutic efficacy and reducing associated toxicities, in mouse models of breast and pancreatic cancers.
{"title":"A sphingolipid-derived paclitaxel nanovesicle enhances efficacy of combination therapies in triple-negative breast cancer and pancreatic cancer","authors":"Zhiren Wang, Wenpan Li, Yanhao Jiang, Teng Ma, Mengwen Li, Shuang Wu, Tuyen Ba Tran, Leyla Estrella Cordova, Ethan Lin, Aaron James Scott, Jennifer Erdrich, Joyce Schroeder, Pavani Chalasani, Jianqin Lu","doi":"10.1038/s43018-025-01029-7","DOIUrl":"10.1038/s43018-025-01029-7","url":null,"abstract":"Taxol and Abraxane, the US Food and Drug Administration-approved paclitaxel (PTX) formulations, have revealed hypersensitivity due to excipients and mediocre efficacy due to insufficient tumor penetration, respectively. Here we developed a sphingolipid-derived PTX nanovesicle (paclitaxome) via covalently conjugating PTX to sphingomyelin, which improved pharmacokinetics and enhanced efficacy in metastatic triple-negative breast cancer and pancreatic cancer female mice and reduced myelosuppression. To bolster tumor penetration and reduce phagocytosis, we engineered a cationization-enabled transcytosis machinery by installing an ultra-pH-sensitive azepane (AZE) probe into paclitaxome and masked nanovesicle surface with a CD47 ‘self’ peptide (CD47p). The resulting CD47p/AZE–paclitaxome synchronized the co-delivery of gemcitabine or carboplatin to boost tumor inhibition and eradicate metastasis in late-stage KPC-Luc pancreatic cancer model and prevent tumor relapse and extend survival in postsurgical 4T1-Luc2 triple-negative breast cancer model in female mice. CD47p/AZE–paclitaxome also outperformed previous promising PTX nanoformulations. Finally, the series of nanoparticle modifications was applied to camptothecin, demonstrating its generalizability. Wang et al. designed sphingomyelin-derived vesicles that deliver paclitaxel to tumor site, improving its therapeutic efficacy and reducing associated toxicities, in mouse models of breast and pancreatic cancers.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1734-1753"},"PeriodicalIF":28.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01029-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961897","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 : 2025-08-19DOI: 10.1038/s43018-025-01023-z
Wies R. Vallentgoed, Youri Hoogstrate, Karin A. van Garderen, Levi van Hijfte, Erik van Dijk, Mathilde C. M. Kouwenhoven, Johanna M. Niers, Kaspar Draaisma, Ivonne Martin, Wendy W. J. de Leng, C. Mircea S. Tesileanu, Iris de Heer, Maud Diepeveen, Anna Lavrova, Paul P. Eijk, Marcel Bühler, Wolfgang Wick, Paul M. Clement, Marc Sanson, Enrico Franceschi, Thierry Gorlia, Vassilis Golfinopoulos, Michael Weller, Tobias Weiss, Pierre A. Robe, Johan M. Kros, Marion Smits, Mark van de Wiel, Bauke Ylstra, Roel G. W. Verhaak, Martin J. van den Bent, Bart A. Westerman, Pieter Wesseling, Pim J. French
The evolutionary processes that drive malignant progression of IDH-mutant astrocytomas remain unclear. Here, we performed multiomics on matched initial and recurrent tumor samples from a cohort of 105 patients and overlaid the data with detailed clinical annotation. We identified overlapping features associated with malignant progression that are derived from three molecular mechanisms: cell cycling, tumor cell (de)differentiation and remodeling of the extracellular matrix. Together, they provide a rationale of the underlying biology of tumor malignancy. DNA methylation levels decreased over time, predominantly in tumors with malignant transformation, and co-occurred with poor prognostic genetic events. We identified a DNA methylation-based signature strongly associated with survival, which allows objective, molecular-based grading of IDH-mutant astrocytomas to aid clinical decision making. Our findings were validated on large, independent cohorts of IDH-mutant astrocytoma samples. Lastly, in this retrospective study, we found little effect of radiotherapy or chemotherapy on the molecular features associated with malignant progression. Vallentgoed et al. integrate clinical and multiomic data from persons with matched initial and recurrent IDH-mutant astrocytomas to identify progression-associated mechanisms and report a DNA methylation-based signature associated with survival.
{"title":"Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling","authors":"Wies R. Vallentgoed, Youri Hoogstrate, Karin A. van Garderen, Levi van Hijfte, Erik van Dijk, Mathilde C. M. Kouwenhoven, Johanna M. Niers, Kaspar Draaisma, Ivonne Martin, Wendy W. J. de Leng, C. Mircea S. Tesileanu, Iris de Heer, Maud Diepeveen, Anna Lavrova, Paul P. Eijk, Marcel Bühler, Wolfgang Wick, Paul M. Clement, Marc Sanson, Enrico Franceschi, Thierry Gorlia, Vassilis Golfinopoulos, Michael Weller, Tobias Weiss, Pierre A. Robe, Johan M. Kros, Marion Smits, Mark van de Wiel, Bauke Ylstra, Roel G. W. Verhaak, Martin J. van den Bent, Bart A. Westerman, Pieter Wesseling, Pim J. French","doi":"10.1038/s43018-025-01023-z","DOIUrl":"10.1038/s43018-025-01023-z","url":null,"abstract":"The evolutionary processes that drive malignant progression of IDH-mutant astrocytomas remain unclear. Here, we performed multiomics on matched initial and recurrent tumor samples from a cohort of 105 patients and overlaid the data with detailed clinical annotation. We identified overlapping features associated with malignant progression that are derived from three molecular mechanisms: cell cycling, tumor cell (de)differentiation and remodeling of the extracellular matrix. Together, they provide a rationale of the underlying biology of tumor malignancy. DNA methylation levels decreased over time, predominantly in tumors with malignant transformation, and co-occurred with poor prognostic genetic events. We identified a DNA methylation-based signature strongly associated with survival, which allows objective, molecular-based grading of IDH-mutant astrocytomas to aid clinical decision making. Our findings were validated on large, independent cohorts of IDH-mutant astrocytoma samples. Lastly, in this retrospective study, we found little effect of radiotherapy or chemotherapy on the molecular features associated with malignant progression. Vallentgoed et al. integrate clinical and multiomic data from persons with matched initial and recurrent IDH-mutant astrocytomas to identify progression-associated mechanisms and report a DNA methylation-based signature associated with survival.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1693-1713"},"PeriodicalIF":28.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883219","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 : 2025-08-18DOI: 10.1038/s43018-025-01037-7
Jessalyn M. Ubellacker, Scott J. Dixon
Ferroptosis is a nonapoptotic form of cell death characterized by lethal membrane lipid peroxidation. This mechanism was first characterized in cancer cells well over a decade ago, and there is much enthusiasm for the concept that certain cancers may be treated by inducing ferroptosis. However, therapies that engage ferroptosis have yet to enter clinical testing. In this Review, we highlight the gap between our rapidly expanding knowledge of the ferroptosis mechanism and its translation into cancer therapies. We discuss the known challenges that may be slowing ferroptosis therapies from reaching the clinic. Ubellacker and Dixon summarize the latest discoveries on ferroptosis in cancer, covering the molecular and cellular pathways underlying sensitivity and resistance to this type of cell death, as well as potential translational applications in cancer therapeutics.
{"title":"Prospects for ferroptosis therapies in cancer","authors":"Jessalyn M. Ubellacker, Scott J. Dixon","doi":"10.1038/s43018-025-01037-7","DOIUrl":"10.1038/s43018-025-01037-7","url":null,"abstract":"Ferroptosis is a nonapoptotic form of cell death characterized by lethal membrane lipid peroxidation. This mechanism was first characterized in cancer cells well over a decade ago, and there is much enthusiasm for the concept that certain cancers may be treated by inducing ferroptosis. However, therapies that engage ferroptosis have yet to enter clinical testing. In this Review, we highlight the gap between our rapidly expanding knowledge of the ferroptosis mechanism and its translation into cancer therapies. We discuss the known challenges that may be slowing ferroptosis therapies from reaching the clinic. Ubellacker and Dixon summarize the latest discoveries on ferroptosis in cancer, covering the molecular and cellular pathways underlying sensitivity and resistance to this type of cell death, as well as potential translational applications in cancer therapeutics.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 8","pages":"1326-1336"},"PeriodicalIF":28.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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