Cancer CellPub Date : 2025-06-05DOI: 10.1016/j.ccell.2025.05.008
Jiachen Hu, Xuejun Jiang
{"title":"When essential metal elements become culprits—Cuproptosis in focus","authors":"Jiachen Hu, Xuejun Jiang","doi":"10.1016/j.ccell.2025.05.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.008","url":null,"abstract":"Recently, a copper-dependent form of cell death called cuproptosis has been described, distinct from apoptosis, ferroptosis, and other known pathways. Cuproptosis is defined by excessive copper binding to lipoylated proteins, causing their aggregation and leading to cell death. Here, we discuss recent advances in understanding cuproptosis, focusing on its molecular mechanisms, physiological regulators, and therapeutic potential in cancer.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"5 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219078","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}
Cancer CellPub Date : 2025-05-29DOI: 10.1016/j.ccell.2025.05.003
Jaco C. Knol, Mengge Lyu, Franziska Böttger, Madalena Nunes Monteiro, Thang V. Pham, Frank Rolfs, Andrea Vallés-Martí, Tim Schelfhorst, Richard R. de Goeij-de Haas, Irene V. Bijnsdorp, Shuaiyao Wang, Fangfei Zhang, Jun A, Bart A. Westerman, Barbara Sitek, Janne Lehtiö, Jan Koster, Jan N.M. IJzermans, Hanneke W.M. van Laarhoven, Maarten F. Bijlsma, Connie R. Jimenez
{"title":"The pan-cancer proteome atlas, a mass spectrometry-based landscape for discovering tumor biology, biomarkers, and therapeutic targets","authors":"Jaco C. Knol, Mengge Lyu, Franziska Böttger, Madalena Nunes Monteiro, Thang V. Pham, Frank Rolfs, Andrea Vallés-Martí, Tim Schelfhorst, Richard R. de Goeij-de Haas, Irene V. Bijnsdorp, Shuaiyao Wang, Fangfei Zhang, Jun A, Bart A. Westerman, Barbara Sitek, Janne Lehtiö, Jan Koster, Jan N.M. IJzermans, Hanneke W.M. van Laarhoven, Maarten F. Bijlsma, Connie R. Jimenez","doi":"10.1016/j.ccell.2025.05.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.003","url":null,"abstract":"Most cancer proteomics studies to date have focused on a single cancer type. We report The Pan-Cancer Proteome Atlas (TPCPA) based on data-independent acquisition mass spectrometry, to better understand cancer biology and identify therapeutic targets and biomarkers. TPCPA includes 9,670 proteins derived from 999 primary tumors representing 22 cancer types. We describe pan-cancer and cancer type-enriched proteins with extensive external annotation, prioritizing candidate drug targets and biomarkers. Relevant for proteolysis-targeting chimeras, we identify E3-ubiquitin ligases highly expressed in specific tumor types, including HERC5 (esophageal cancer) and RNF5 (liver cancer). Co-expression analysis reveals 13 modules, including unexpected hub proteins as potential drug targets (e.g., GFPT1, LRPPRC, PINK1, DOCK2, and PTPN6). Analysis of 195 colorectal cancers identifies protein markers for RNA-based consensus molecular subtypes (CMSs) and two immune subtypes with prognostic value. We report a cancer type classifier for identification of cancers of unknown primary origin. All TPCPA data can be queried in a dedicated web resource.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"31 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165276","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}
Cancer CellPub Date : 2025-05-29DOI: 10.1016/j.ccell.2025.05.002
Andrew W. Daman, Anthony C. Antonelli, Gil Redelman-Sidi, Lucinda Paddock, Shireen Khayat, Mythili Ketavarapu, Jin Gyu Cheong, Leonardo F. Jurado, Anna Benjamin, Song Jiang, Dughan Ahimovic, Victoria R. Lawless, Michael J. Bale, Oleg Loutochin, Victor A. McPherson, Maziar Divangahi, Rachel E. Niec, Dana Pe’er, Eugene Pietzak, Steven Z. Josefowicz, Michael S. Glickman
{"title":"Microbial cancer immunotherapy reprograms hematopoiesis to enhance myeloid-driven anti-tumor immunity","authors":"Andrew W. Daman, Anthony C. Antonelli, Gil Redelman-Sidi, Lucinda Paddock, Shireen Khayat, Mythili Ketavarapu, Jin Gyu Cheong, Leonardo F. Jurado, Anna Benjamin, Song Jiang, Dughan Ahimovic, Victoria R. Lawless, Michael J. Bale, Oleg Loutochin, Victor A. McPherson, Maziar Divangahi, Rachel E. Niec, Dana Pe’er, Eugene Pietzak, Steven Z. Josefowicz, Michael S. Glickman","doi":"10.1016/j.ccell.2025.05.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.002","url":null,"abstract":"<em>Mycobacterium bovis</em> Bacillus Calmette-Guérin (BCG) is the vaccine against tuberculosis and an immunotherapy for bladder cancer. When administered intravenously, BCG reprograms bone marrow hematopoietic stem and progenitor cells (HSPCs), leading to heterologous protection against infections. Whether HSPC reprogramming contributes to the anti-tumor effects of BCG administered into the bladder is unknown. We demonstrate that BCG administered in the bladder colonizes the bone marrow and, in both mice and humans, reprograms HSPCs to alter and amplify myelopoiesis. BCG-reprogrammed HSPCs are sufficient to confer augmented anti-tumor immunity through production of neutrophils, monocytes, and dendritic cells that broadly remodel the tumor microenvironment, drive T cell-dependent anti-tumor responses, and synergize with checkpoint blockade. We conclude that bladder BCG acts systemically through hematopoiesis, highlighting the broad potential of HSPC reprogramming to enhance the innate drivers of T cell-dependent tumor immunity.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"29 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165271","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}
Cancer CellPub Date : 2025-05-27DOI: 10.1016/j.ccell.2025.05.007
Toshiro Hara, Rony Chanoch-Myers, Nathan D. Mathewson, Chad Myskiw, Lyla Atta, Lillian Bussema, Stephen W. Eichhorn, Alissa C. Greenwald, Gabriela S. Kinker, Christopher Rodman, L. Nicolas Gonzalez Castro, Hiroaki Wakimoto, Orit Rozenblatt-Rosen, Xiaowei Zhuang, Jean Fan, Tony Hunter, Inder M. Verma, Kai W. Wucherpfennig, Aviv Regev, Mario L. Suvà, Itay Tirosh
{"title":"Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma","authors":"Toshiro Hara, Rony Chanoch-Myers, Nathan D. Mathewson, Chad Myskiw, Lyla Atta, Lillian Bussema, Stephen W. Eichhorn, Alissa C. Greenwald, Gabriela S. Kinker, Christopher Rodman, L. Nicolas Gonzalez Castro, Hiroaki Wakimoto, Orit Rozenblatt-Rosen, Xiaowei Zhuang, Jean Fan, Tony Hunter, Inder M. Verma, Kai W. Wucherpfennig, Aviv Regev, Mario L. Suvà, Itay Tirosh","doi":"10.1016/j.ccell.2025.05.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.05.007","url":null,"abstract":"(Cancer Cell <em>39</em>, 779–792.e1–e11; June 14, 2021)","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"239 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145856","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}
Cancer CellPub Date : 2025-05-15DOI: 10.1016/j.ccell.2025.04.014
Shiekh Tanveer Ahmad, Yiran Li, Jesus Garcia-Lopez, Brian L. Gudenas, Jennifer Hadley, Leena Paul, Stephanie C. Wu, Alaa Refaat, Marija Kojic, Melissa Batts, Taha Soliman, Aaron Pitre, Frederik Arnskötter, Frederique Zindy, Alun Jones, Nathaniel R. Twarog, Anand Mayasundari, Brandon Bianski, Christopher Tinkle, Abbas Shirinifard, Paul A. Northcott
{"title":"Genetic modeling of ELP1-associated Sonic hedgehog medulloblastoma identifies MDM2 as a selective therapeutic target","authors":"Shiekh Tanveer Ahmad, Yiran Li, Jesus Garcia-Lopez, Brian L. Gudenas, Jennifer Hadley, Leena Paul, Stephanie C. Wu, Alaa Refaat, Marija Kojic, Melissa Batts, Taha Soliman, Aaron Pitre, Frederik Arnskötter, Frederique Zindy, Alun Jones, Nathaniel R. Twarog, Anand Mayasundari, Brandon Bianski, Christopher Tinkle, Abbas Shirinifard, Paul A. Northcott","doi":"10.1016/j.ccell.2025.04.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.04.014","url":null,"abstract":"Germline loss-of-function (LOF) variants in <em>Elongator acetyltransferase complex subunit 1 (ELP1)</em> are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ∼30% of the Sonic hedgehog (SHH) 3 subtype. The mechanism(s) by which germline <em>ELP1</em> deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous <em>Elp1</em> LOF (<em>Elp1</em><sub><em>HET</em></sub><em>)</em> seen in affected germline carriers exhibit hallmark features of premalignancy in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of <em>Elp1</em><sub><em>HET</em></sub> GNPs harboring somatic <em>Ptch1</em> inactivation yields SHH-MB-like tumors with compromised p53 signaling, providing a plausible explanation for the exclusivity of <em>ELP1-</em>associated MBs in the SHH-3 subtype. Preclinical treatment of <em>ELP1</em>-mutant patient-derived xenografts with an FDA-approved MDM2 inhibitor reactivates p53-dependent apoptosis and extends survival. Our findings functionally substantiate the role of <em>ELP1</em> deficiency in SHH-MB predisposition and nominate therapeutics targeting MDM2 as a rational treatment option.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"13 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980018","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}
Cancer CellPub Date : 2025-05-15DOI: 10.1016/j.ccell.2025.04.013
Derek Dang, Akash Deogharkar, John McKolay, Kyle S. Smith, Pooja Panwalkar, Simon Hoffman, Wentao Tian, Sunjong Ji, Ana P. Azambuja, Siva Kumar Natarajan, Joanna Lum, Jill Bayliss, Katie Manzeck, Stefan R. Sweha, Erin Hamanishi, Matthew Pun, Diya Patel, Sagar Rau, Olamide Animasahun, Abhinav Achreja, Sriram Venneti
{"title":"Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis","authors":"Derek Dang, Akash Deogharkar, John McKolay, Kyle S. Smith, Pooja Panwalkar, Simon Hoffman, Wentao Tian, Sunjong Ji, Ana P. Azambuja, Siva Kumar Natarajan, Joanna Lum, Jill Bayliss, Katie Manzeck, Stefan R. Sweha, Erin Hamanishi, Matthew Pun, Diya Patel, Sagar Rau, Olamide Animasahun, Abhinav Achreja, Sriram Venneti","doi":"10.1016/j.ccell.2025.04.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.04.013","url":null,"abstract":"MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth <em>in vivo</em> in multiple group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill group-3 MB by cuproptosis.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"145 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980019","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}
Cancer CellPub Date : 2025-05-12DOI: 10.1016/j.ccell.2025.04.012
Monika Julia Wolf, Alexandra Hoos, Judith Bauer, Steffen Boettcher, Markus Knust, Achim Weber, Nicole Simonavicius, Christoph Schneider, Matthias Lang, Michael Stürzl, Roland S. Croner, Andreas Konrad, Markus G. Manz, Holger Moch, Adriano Aguzzi, Geert van Loo, Manolis Pasparakis, Marco Prinz, Lubor Borsig, Mathias Heikenwalder
{"title":"Endothelial CCR2 Signaling Induced by Colon Carcinoma Cells Enables Extravasation via the JAK2-Stat5 and p38MAPK Pathway","authors":"Monika Julia Wolf, Alexandra Hoos, Judith Bauer, Steffen Boettcher, Markus Knust, Achim Weber, Nicole Simonavicius, Christoph Schneider, Matthias Lang, Michael Stürzl, Roland S. Croner, Andreas Konrad, Markus G. Manz, Holger Moch, Adriano Aguzzi, Geert van Loo, Manolis Pasparakis, Marco Prinz, Lubor Borsig, Mathias Heikenwalder","doi":"10.1016/j.ccell.2025.04.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.04.012","url":null,"abstract":"(Cancer Cell <em>22</em>, 91–105; July 10, 2012)","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"51 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933505","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}
Cancer CellPub Date : 2025-05-12DOI: 10.1016/j.ccell.2025.04.008
Tian V. Tian, Silvia Affò
{"title":"Stromal barriers to the abscopal effect","authors":"Tian V. Tian, Silvia Affò","doi":"10.1016/j.ccell.2025.04.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.04.008","url":null,"abstract":"In this issue of <em>Cancer Cell</em>, Zhang et al. reveal that PAI-1-induced SFRP2<sup>high</sup> cancer-associated fibroblasts reduce the abscopal effect of radioimmunotherapy. Targeting PAI-1 or SFRP2 enhances T cell recruitment and prevents the formation of an immunosuppressive perivascular niche, improving radioimmunotherapy’s abscopal effect.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"8 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143933503","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}
Cancer CellPub Date : 2025-05-08DOI: 10.1016/j.ccell.2025.04.007
Hannah Garner, Moreno Martinovic, Ning Qing Liu, Noor A.M. Bakker, Irene Querol Velilla, Cheei-Sing Hau, Kim Vrijland, Daphne Kaldenbach, Marleen Kok, Elzo de Wit, Karin E. de Visser
{"title":"Understanding and reversing mammary tumor-driven reprogramming of myelopoiesis to reduce metastatic spread","authors":"Hannah Garner, Moreno Martinovic, Ning Qing Liu, Noor A.M. Bakker, Irene Querol Velilla, Cheei-Sing Hau, Kim Vrijland, Daphne Kaldenbach, Marleen Kok, Elzo de Wit, Karin E. de Visser","doi":"10.1016/j.ccell.2025.04.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2025.04.007","url":null,"abstract":"Tumor-induced systemic accumulation and polarization of neutrophils to an immunosuppressive phenotype is a potent driver of metastasis formation. Yet, how mammary tumors reprogram granulopoiesis at the molecular level and when tumor imprinting occurs during neutrophil development remains underexplored. Here, we combined single-cell, chromatin and functional analyses to unravel the tumor-driven reprogramming of granulopoiesis in the bone marrow, along with intervention studies aimed at reversing this process. We observe that mammary tumors accelerate commitment to the neutrophil lineage at the expense of lymphopoiesis and erythropoiesis without stimulating the development of a novel myeloid lineage. Moreover, tumor-directed immunosuppressive imprinting of neutrophils starts early in hematopoiesis. Treatment with anti-IL-1β normalizes tumor-induced granulopoiesis, reducing neutrophil immunosuppressive phenotype and mitigating metastatic spread. Together, these data provide molecular insights into the aberrant, tumor-driven neutrophil differentiation pathway leading to metastasis-promoting chronic inflammation and how it can be reversed to reduce metastatic spread.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"49 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920769","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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