Cancer discoveryPub Date : 2025-10-02DOI: 10.1158/2159-8290.cd-25-0947
Yang Bai,Albert S Agustinus,Shira Yomtoubian,Cem Meydan,Dylan R McNally,Liron Yoffe,Melissa J Hubisz,Marvel Tranquille,Sneha Pramod,Christy Hong,Magdalena L Plasilova,Aakanksha R Kapoor,Arshdeep Singh,Henry Withers,Lukas E Dow,Ashley M Laughney,Bhavneet Bhinder,Olivier Elemento,Ari M Melnick,Samuel F Bakhoum,Vivek Mittal
{"title":"Epigenetic regulation of chromosomal instability by EZH2 methyltransferase.","authors":"Yang Bai,Albert S Agustinus,Shira Yomtoubian,Cem Meydan,Dylan R McNally,Liron Yoffe,Melissa J Hubisz,Marvel Tranquille,Sneha Pramod,Christy Hong,Magdalena L Plasilova,Aakanksha R Kapoor,Arshdeep Singh,Henry Withers,Lukas E Dow,Ashley M Laughney,Bhavneet Bhinder,Olivier Elemento,Ari M Melnick,Samuel F Bakhoum,Vivek Mittal","doi":"10.1158/2159-8290.cd-25-0947","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0947","url":null,"abstract":"Chromosomal instability (CIN) and epigenetic reprogramming are central drivers of breast cancer progression, yet the mechanisms connecting them remain elusive. We uncover a direct role of EZH2 histone methyltransferase in promoting CIN in triple-negative breast cancer (TNBC). Across breast cancers, EZH2 expression correlates with copy number alterations, and its catalytic activity is associated with increased CIN in metastasis-initiating cells. Pharmacological EZH2 inhibition suppressed CIN, revealing an unexpected vulnerability. Integrated chromatin and transcriptome profiling identified Tankyrase (TNKS), a poly(ADP-ribose) polymerase, as a direct transcriptional target of EZH2. Mechanistically, EZH2-mediated TNKS suppression disrupts CPAP (centrosomal P4.1-associated protein), driving centrosome overduplication, multipolar mitosis and exacerbated CIN. In vivo, CIN suppression is a critical mechanism underlying the anti-metastatic effects of EZH2 inhibition. These findings delineate a previously unrecognized epigenetic mechanism governing CIN and establish EZH2 inhibitors as the first therapeutic agents capable of directly suppressing CIN, underscoring the need for trials with metastasis-focused endpoints.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"22 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203566","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 discoveryPub Date : 2025-10-01DOI: 10.1158/2159-8290.CD-24-1590
Divij Verma, Rachel Zeig-Owens, David G Goldfarb, Leah Kravets, Kith Pradhan, Bradley Rockwell, Srabani Sahu, Susheian Kelly, Orsi Giricz, Sakshi Jasra, Yiyu Zou, Colette Prophete, Lidiane S Torres, Srinivas Aluri, Samarpana Chakraborty, Rajni Kumari, Shanisha Gordon-Mitchell, Jingli Wang, Alexander J Silver, Taylor M South, Sarah D Olmstead, Charles B Hall, Simone Sidoli, Ryan Bender, Ola Landgren, Lee M Greenberger, Amittha Wickrema, Advaitha Madireddy, Aditi Shastri, Eric M Pietras, Lindsay M LaFave, Anna Nolan, Mitchell D Cohen, Michael R Savona, Ulrich Steidl, David J Prezant, Amit Verma
{"title":"Elevated clonal hematopoiesis in 9/11 first responders has distinct age-related patterns and relies on IL1RAP for clonal expansion.","authors":"Divij Verma, Rachel Zeig-Owens, David G Goldfarb, Leah Kravets, Kith Pradhan, Bradley Rockwell, Srabani Sahu, Susheian Kelly, Orsi Giricz, Sakshi Jasra, Yiyu Zou, Colette Prophete, Lidiane S Torres, Srinivas Aluri, Samarpana Chakraborty, Rajni Kumari, Shanisha Gordon-Mitchell, Jingli Wang, Alexander J Silver, Taylor M South, Sarah D Olmstead, Charles B Hall, Simone Sidoli, Ryan Bender, Ola Landgren, Lee M Greenberger, Amittha Wickrema, Advaitha Madireddy, Aditi Shastri, Eric M Pietras, Lindsay M LaFave, Anna Nolan, Mitchell D Cohen, Michael R Savona, Ulrich Steidl, David J Prezant, Amit Verma","doi":"10.1158/2159-8290.CD-24-1590","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1590","url":null,"abstract":"<p><p>Environmental exposures are linked to precancerous hematologic conditions, but studies in cohorts with well-defined exposures are limited. We sequenced blood samples from a large cohort of first-responders exposed to the aerosolized dust and carcinogens from the 9/11 World Trade Center (WTC) disaster and observed a significantly higher prevalence of clonal hematopoiesis (CH) mutations when compared to two sets of control cohorts after controlling for age, race, and sex. Younger exposed first-responders exhibited unconventional CH mutations, with defective DNA repair signatures. Leukemia risk was elevated (3.7% vs. 0.6%, OR=5.73) in WTC-exposed responders with CH versus without CH. Exposure to particulate matter collected from WTC site impaired healthy stem cell while expanding Tet2-mutant CH clones in mice. Inflammation sensor, IL1RAP, was overexpressed in murine CH, and genetic knockdown inhibited mutant clone growth in-vivo. This study links discrete environmental exposure to hematopoietic mutations and leukemia, identifying IL1RAP as a novel therapeutic target in CH.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":33.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198486","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 discoveryPub Date : 2025-09-25DOI: 10.1158/2159-8290.cd-24-1565
Yuning J. Tang, Haiqing Xu, Nicholas W. Hughes, Paloma Ruiz, Samuel H. Kim, Emily G. Shuldiner, Steven S. Lopez, Jess D. Hebert, Saswati Karmakar, Laura Andrejka, Deniz Nesli Dolcen, Gabor Boross, Pauline Chu, Christian A. Kunder, Colin Detrick, Sarah E. Pierce, Emily L. Ashkin, William J. Greenleaf, Anne K. Voss, Tim Thomas, Matt van de Rijn, Dmitri A. Petrov, Monte M. Winslow
{"title":"Functional mapping of epigenomic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes","authors":"Yuning J. Tang, Haiqing Xu, Nicholas W. Hughes, Paloma Ruiz, Samuel H. Kim, Emily G. Shuldiner, Steven S. Lopez, Jess D. Hebert, Saswati Karmakar, Laura Andrejka, Deniz Nesli Dolcen, Gabor Boross, Pauline Chu, Christian A. Kunder, Colin Detrick, Sarah E. Pierce, Emily L. Ashkin, William J. Greenleaf, Anne K. Voss, Tim Thomas, Matt van de Rijn, Dmitri A. Petrov, Monte M. Winslow","doi":"10.1158/2159-8290.cd-24-1565","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1565","url":null,"abstract":"Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We employed a novel high-throughput in vivo method to perform iterative functional screens of &gt;250 epigenomic regulators within autochthonous oncogenic KRAS-driven lung tumors. We identified many previously unappreciated epigenomic tumor-suppressor and tumor-dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung adenocarcinoma. Histone modifications generated by HBO1 complex are frequently reduced in human lung adenocarcinomas and are associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, impact chromatin accessibility, and control the expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results provide a phenotypic roadmap of epigenomic regulators in lung tumorigenesis in vivo.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"99 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140870","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 discoveryPub Date : 2025-09-25DOI: 10.1158/2159-8290.cd-24-1669
Iris L Mimpen,Thomas W Battaglia,Miguel Parra Martinez,Catherine Toner-Bartelds,Laurien J Zeverijn,Birgit S Geurts,Karlijn Verkerk,Louisa R Hoes,Allard W J van Renterghem,Michael Noe,Ingrid Hofland,Annegien Broeks,Vincent van der Noort,Edwin C A Stigter,Can M C Gulersonmez,Boudewijn M T Burgering,Merel van Gogh,Marcel R de Zoete,Hans Gelderblom,Krijn K Dijkstra,Lodewyk F A Wessels,Emile E Voest
{"title":"Microbial metabolic pathways guide response to immune checkpoint blockade therapy.","authors":"Iris L Mimpen,Thomas W Battaglia,Miguel Parra Martinez,Catherine Toner-Bartelds,Laurien J Zeverijn,Birgit S Geurts,Karlijn Verkerk,Louisa R Hoes,Allard W J van Renterghem,Michael Noe,Ingrid Hofland,Annegien Broeks,Vincent van der Noort,Edwin C A Stigter,Can M C Gulersonmez,Boudewijn M T Burgering,Merel van Gogh,Marcel R de Zoete,Hans Gelderblom,Krijn K Dijkstra,Lodewyk F A Wessels,Emile E Voest","doi":"10.1158/2159-8290.cd-24-1669","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1669","url":null,"abstract":"Studies have identified a link between specific microbiome-derived bacteria and immune checkpoint blockade (ICB) efficacy. However, these species lack consistency across studies and their immunomodulatory mechanisms remain elusive. To understand the influence of the microbiome on ICB response we studied its functional capacity. Using pan-cancer metagenomics data of ICB-treated patients, we showed that community-level metabolic pathways are stable across individuals, making them suitable to predict ICB response. We identified several microbial metabolic processes significantly associated with response, including the methylerythritol phosphate (MEP) pathway, which was associated with response and induced Vδ2 T cell-mediated anti-tumor responses in patient-derived tumor organoids. In contrast, riboflavin synthesis was associated with ICB resistance, and its intermediates induced mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Moreover, gut metabolomics revealed that high riboflavin levels were linked to worse survival in patients with abundant intratumoral MAIT cells. Collectively, our results highlight the relevance of metabolite-mediated microbiome-immune cell crosstalk.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"41 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134318","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 discoveryPub Date : 2025-09-23DOI: 10.1158/2159-8290.cd-24-1417
Alberto Diaz-Jimenez, Emily G. Shuldiner, Kalman Somogyi, Karen Shih, Oscar Gonzalez-Velasco, Mulham Najajreh, Stewart Kim, Filiz Akkas, Christopher W. Murray, Laura Andrejka, Min K. Tsai, Benedikt Brors, Ilse Hofmann, Smruthy Sivakumar, Saumya D. Sisoudiya, Ethan S. Sokol, Hongchen Cai, Dmitri A. Petrov, Monte M. Winslow, Rocio Sotillo
{"title":"EML4-ALK variant-specific genetic interactions shape lung tumorigenesis","authors":"Alberto Diaz-Jimenez, Emily G. Shuldiner, Kalman Somogyi, Karen Shih, Oscar Gonzalez-Velasco, Mulham Najajreh, Stewart Kim, Filiz Akkas, Christopher W. Murray, Laura Andrejka, Min K. Tsai, Benedikt Brors, Ilse Hofmann, Smruthy Sivakumar, Saumya D. Sisoudiya, Ethan S. Sokol, Hongchen Cai, Dmitri A. Petrov, Monte M. Winslow, Rocio Sotillo","doi":"10.1158/2159-8290.cd-24-1417","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1417","url":null,"abstract":"Diverse fusions of EML4 and ALK are oncogenic drivers in lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. Here, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes rather than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion-driven cancers.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"11 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127730","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}
{"title":"Development and Prospective Validation of a Cell-free DNA-based Model for the Early Detection of Pancreatic Cancer","authors":"Xiuchao Wang, Hongwei Wang, Meng Zhang, Huikai Li, Yang Liu, HanFei Huang, Jinlong Pei, Jing Huang, Fenglin Zang, Yanhui Zhang, Xingyun Chen, Song Gao, Tiansuo Zhao, Jian Wang, Weidong Ma, Yuexiang Liang, Shangheng Shi, Shuo Li, Wei Li, Tianxing Zhou, Ying Zhang, Xiaonan Cui, Zhao-Xiang Ye, Yan Sun, Li Peng, Xiao Hu, Zhitao Li, Hao Zhang, Dongqin Zhu, Shuang Chang, Jiangyan Zhang, Ruowei Yang, Hua Bao, Xue Wu, Yang Shao, Jun Yu, Chuntao Gao, Yunfeng Cui, Jihui Hao","doi":"10.1158/2159-8290.cd-25-0323","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0323","url":null,"abstract":"Pancreatic cancer (PC) remains a highly lethal malignancy due to late-stage diagnosis and limited therapeutic options. This study presents the development and validation of a non-invasive circulating cell-free DNA (cfDNA)-based model for early PC detection. In a case-control study comprising 232 PC patients and 235 healthy controls, the model demonstrated high diagnostic accuracy (AUC=0.9799 in training; 0.9622 in validation). A prospective cohort study involving 1,926 individuals with diabetes and obesity, established risk factors for PC, further assessed its clinical applicability. The model detected 75% of PC cases, including all Stage 0 patients, with a lead time of up to 298 days, significantly outperforming CA19-9. Additionally, it demonstrates potential for distinguishing high-risk from low-risk pancreatic cysts, thereby facilitating more precise risk stratification. This study highlights the potential of cfDNA-based screening as a scalable, non-invasive tool for early PC detection, warranting further large-scale clinical validation to enhance patient outcomes.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"33 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116326","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 discoveryPub Date : 2025-09-22DOI: 10.1158/2159-8290.cd-24-0556
Marco Avolio,Simonetta M Leto,Francesco Sassi,Barbara Lupo,Elena Grassi,Irene Catalano,Eugenia R Zanella,Valentina Vurchio,Francesca Cottino,Petros K Tsantoulis,Luca Lazzari,Paolo Luraghi,Martina Ferri,Francesco Galimi,Enrico Berrino,Sara E Bellomo,Marco Viviani,Alberto Sogari,Gianluca Mauri,Federica Tosi,Federica Cruciani,Andrea Sartore-Bianchi,Salvatore Siena,Felice Borghi,Valter Torri,Elena Élez,Josep Tabernero,Maria Nieva,Clara Montagut,Noelia Tarazona,Andres Cervantes,Sabine Tejpar,Alberto Bardelli,Caterina Marchiò,Silvia Marsoni,Andrea Bertotti,Livio Trusolino
{"title":"The molecular and functional landscape of resistance to FOLFIRI chemotherapy in metastatic colorectal cancer.","authors":"Marco Avolio,Simonetta M Leto,Francesco Sassi,Barbara Lupo,Elena Grassi,Irene Catalano,Eugenia R Zanella,Valentina Vurchio,Francesca Cottino,Petros K Tsantoulis,Luca Lazzari,Paolo Luraghi,Martina Ferri,Francesco Galimi,Enrico Berrino,Sara E Bellomo,Marco Viviani,Alberto Sogari,Gianluca Mauri,Federica Tosi,Federica Cruciani,Andrea Sartore-Bianchi,Salvatore Siena,Felice Borghi,Valter Torri,Elena Élez,Josep Tabernero,Maria Nieva,Clara Montagut,Noelia Tarazona,Andres Cervantes,Sabine Tejpar,Alberto Bardelli,Caterina Marchiò,Silvia Marsoni,Andrea Bertotti,Livio Trusolino","doi":"10.1158/2159-8290.cd-24-0556","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0556","url":null,"abstract":"The combination of 5-fluorouracil and irinotecan (FOLFIRI) remains a standard-of-care treatment for metastatic colorectal cancer (mCRC), yet benefits only about half of patients. Using patient-derived xenografts (PDXs), we investigated the biological underpinnings of this heterogeneous response. FOLFIRI-resistant models showed transcriptional upregulation of innate immunity and mitochondrial metabolism genes, together with reduced expression of the DNA polymerase POLD1. Sensitive counterparts exhibited a BRCAness-like phenotype with genomic scars of homologous recombination (HR) deficiency, not caused by genetic or epigenetic loss of HR genes but by low abundance of the RAD51 recombinase. In tumoroids, forced RAD51 overexpression attenuated HR deficiency-related scars and chemotherapy-induced damage, while HR inhibition through ATM blockade enhanced drug sensitivity. The predictive relevance of key response determinants was validated in clinical samples. This work illuminates functional, non-genetic facets of BRCAness in mCRC and introduces actionable biomarkers and targets, offering prospects to improve clinical decision-making and broaden therapeutic options for chemorefractory patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"50 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103344","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}
{"title":"Activation of T cell-intrinsic p53 by acetylation elicits antitumor immunity to boost cancer immunotherapy.","authors":"Xiaojun Yan,Wenbin Xu,Han Yao,Zhen Wu,Jingyuan Ning,Shidong Zhao,Yajing Liu,Meng Zhang,Dongkui Xu,Zhanlong Shen,Wei Gu,Donglai Wang","doi":"10.1158/2159-8290.cd-25-0649","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0649","url":null,"abstract":"Although p53 plays a central role in tumor suppression, how it is regulated in T cells to exert antitumor effects remains unclear. Here, we show that activation of T cell-intrinsic p53 via carboxyl-terminal domain (CTD) acetylation during immunotherapy activates the IFN-γ pathway, promotes CD8+ T cell infiltration, and elicits CD8+ T cell-dependent antitumor immunity. Using T cell-specific knockin mouse models, we demonstrate that loss of CTD acetylation in T cells abrogates CD8+ T cell-dependent antitumor immunity whereas expression of CTD acetylation-mimicking p53 in T cells enhances this immune response. Moreover, we identify IFNG as a direct target of T cell-intrinsic p53 and uncover a positive feedback loop between p53 and the IFN-γ pathway for enhancing T cell-dependent antitumor immunity. Our study reveals that CTD acetylation-mediated activation of T cell-intrinsic p53 promotes antitumor immunity in response to immunotherapy, highlighting a non-tumor cell-autonomous mechanism of p53 action by regulating adoptive immune responses.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"9 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083437","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 discoveryPub Date : 2025-09-08DOI: 10.1158/2159-8290.cd-25-0526
Alyssa Shepard,Daniel K Lester,Scott Troutman,Sany Hoxha,Walid T Khaled,Ewan St J Smith,Thomas J Park,Rochelle Buffenstein,Dongliang Du,Mingxiang Teng,Christine M Dengler-Crish,Kenneth Y Tsai,Elsa R Flores,Andrea Ventura,Joseph L Kissil
{"title":"An Autochthonous Model of Lung Cancer Identifies Requirements for Cellular Transformation in the Naked Mole-Rat.","authors":"Alyssa Shepard,Daniel K Lester,Scott Troutman,Sany Hoxha,Walid T Khaled,Ewan St J Smith,Thomas J Park,Rochelle Buffenstein,Dongliang Du,Mingxiang Teng,Christine M Dengler-Crish,Kenneth Y Tsai,Elsa R Flores,Andrea Ventura,Joseph L Kissil","doi":"10.1158/2159-8290.cd-25-0526","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0526","url":null,"abstract":"There is growing interest in understanding the mechanisms underlying differences in cancer incidence among species (comparative oncology). The naked mole-rat (NMR) is often referenced as \"cancer-resistant\" and prior studies focused on identifying mechanisms explaining this. However, efforts to assess this in vivo have been limited. Herein, we provide evidence that the NMR presents as a novel autochthonous model of lung tumor initiation, driven by an introduction of the oncogenic Eml4-Alk fusion protein using CRISPR-mediated genome editing. Whereas in mice the inversion alone is sufficient to drive tumorigenesis, the inversion alone was insufficient to drive tumorigenesis in the NMR lung and tumor development required additional losses of the tumor suppressors p53 and pRb. Our findings suggest that the proposed \"resistance\" of the NMR to the development of cancer may reflect that the genetic events leading to tumor initiation are likely to be comparable to those present in human cells.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"51 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008789","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 discoveryPub Date : 2025-09-04DOI: 10.1158/2159-8290.cd-25-1042
Felipe Galvez-Cancino,Maria Armero,David R Withers,Paula Molero-Glez,Ana Melero,Belen Palencia,Ignacio Melero
{"title":"The Dark Side of NK Cells in Cancer Immunotherapy.","authors":"Felipe Galvez-Cancino,Maria Armero,David R Withers,Paula Molero-Glez,Ana Melero,Belen Palencia,Ignacio Melero","doi":"10.1158/2159-8290.cd-25-1042","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1042","url":null,"abstract":"NK cells are a subset of innate lymphoid cells originally identified in mice and humans based on their ability to mediate cytotoxicity against transformed cells. However, two recent back-to-back studies in this issue of Cancer Discovery reveal that NK cell infiltration is not always beneficial; rather, it can impair the efficacy of immune checkpoint blockade through immune-regulatory mechanisms. See related article by Pozniak et al., p. 1819 See related article by Song et al., p. 1835.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"1206 1","pages":"1777-1779"},"PeriodicalIF":28.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960095","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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