Cancer discoveryPub Date : 2025-04-15DOI: 10.1158/2159-8290.cd-24-0234
Hyun Jung Kim, Keon Woo Kim, Do Hyeon Cha, Jihwan Yoo, Eui Hyun Kim, Jong Hee Chang, Seok-Gu Kang, Jung Won Park, Ja Hye Kim, Yeonhee Lee, Eunha Lim, Yiseul Kim, Myeong Heui Kim, Xue Li, Joo Ho Lee, Jeong Ho Lee
{"title":"Precancerous Cells Initiate Glioblastoma Evolution and Contribute to Intratumoral Heterogeneity","authors":"Hyun Jung Kim, Keon Woo Kim, Do Hyeon Cha, Jihwan Yoo, Eui Hyun Kim, Jong Hee Chang, Seok-Gu Kang, Jung Won Park, Ja Hye Kim, Yeonhee Lee, Eunha Lim, Yiseul Kim, Myeong Heui Kim, Xue Li, Joo Ho Lee, Jeong Ho Lee","doi":"10.1158/2159-8290.cd-24-0234","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0234","url":null,"abstract":"Neural stem cells (NSCs) in the subventricular zone (SVZ) are identified as cells-of-origin harboring driver mutations in glioblastoma (GBM), which is the most devastating brain tumor with highly heterogeneous nature. However, the sequential transformation of a limited number of mutation-harboring NSCs into a distant tumor with high intratumoral heterogeneity remains poorly understood. In this study, we have identified transcriptionally distinct types of mutation-harboring precancerous cells in our spontaneous, somatic mouse model recapitulating human GBM evolution as well as in tumor-free SVZ tissues from patients. These precancerous cells emerge via oligodendrocyte lineage specification, exhibiting unique transcriptional programs involving dysregulated translations and extracellular matrix remodeling. Subsequently, they give rise to heterogeneous tumor cell populations by activating multiple programs crucial for gliomagenesis. Our findings highlight the pivotal role of precancerous cells in tumor evolution and intratumoral heterogeneity, suggesting their potential as a novel therapeutic target for GBM.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"26 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836682","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 : 2025-04-08DOI: 10.1158/2159-8290.cd-24-0943
Carlota Arenillas, Lucía Celada, José Ruiz-Cantador, Bruna Calsina, Debayan Datta, Eduardo García-Galea, Roberta Fasani, Ana Belén Moreno-Cárdenas, Juan José Alba-Linares, Berta Miranda-Barrio, Ángel M. Martínez-Montes, Cristina Alvarez-Escola, Beatriz Lecumberri, Ana González García, Shahida K. Flores, Emmanuel Esquivel, Yanli Ding, Mirko Peitzsch, José-Ángel Robles-Guirado, Rita Maria Regojo Zapata, José Juan Pozo-Kreilinger, Carmela Iglesias, Trisha Dwight, Christopher A. Muir, Amelia Oleaga, Maria Elvira Garrido-Lestache Rodríguez-Monte, Maria Jesús Del Cerro, Isaac Martínez-Bendayán, Enol Álvarez-González, Tamara Cubiella, Delmar Muniz Lourenço, Maria Adelaide A. Pereira, Nelly Burnichon, Alexandre Buffet, Craig Broberg, Paxton V. Dickson, Mario F. Fraga, José Luis Llorente Pendás, Joaquín Rueda Soriano, Francisco Buendía Fuentes, Sergio P.A. Toledo, Roderick Clifton-Bligh, Rodrigo Dienstmann, Josep Villanueva, Jaume Capdevila, Anne-Paule Gimenez-Roqueplo, Judith Favier, Paolo Nuciforo, William F. Young, Nicole Bechmann, Alexander R. Opotowsky, Anand Vaidya, Irina Bancos, Donate Weghorn, Mercedes Robledo, Anna Casteràs, Laura Dos-Subirà, Igor Adameyko, María-Dolores Chiara, Patricia L.M. Dahia, Rodrigo A. Toledo
{"title":"Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes","authors":"Carlota Arenillas, Lucía Celada, José Ruiz-Cantador, Bruna Calsina, Debayan Datta, Eduardo García-Galea, Roberta Fasani, Ana Belén Moreno-Cárdenas, Juan José Alba-Linares, Berta Miranda-Barrio, Ángel M. Martínez-Montes, Cristina Alvarez-Escola, Beatriz Lecumberri, Ana González García, Shahida K. Flores, Emmanuel Esquivel, Yanli Ding, Mirko Peitzsch, José-Ángel Robles-Guirado, Rita Maria Regojo Zapata, José Juan Pozo-Kreilinger, Carmela Iglesias, Trisha Dwight, Christopher A. Muir, Amelia Oleaga, Maria Elvira Garrido-Lestache Rodríguez-Monte, Maria Jesús Del Cerro, Isaac Martínez-Bendayán, Enol Álvarez-González, Tamara Cubiella, Delmar Muniz Lourenço, Maria Adelaide A. Pereira, Nelly Burnichon, Alexandre Buffet, Craig Broberg, Paxton V. Dickson, Mario F. Fraga, José Luis Llorente Pendás, Joaquín Rueda Soriano, Francisco Buendía Fuentes, Sergio P.A. Toledo, Roderick Clifton-Bligh, Rodrigo Dienstmann, Josep Villanueva, Jaume Capdevila, Anne-Paule Gimenez-Roqueplo, Judith Favier, Paolo Nuciforo, William F. Young, Nicole Bechmann, Alexander R. Opotowsky, Anand Vaidya, Irina Bancos, Donate Weghorn, Mercedes Robledo, Anna Casteràs, Laura Dos-Subirà, Igor Adameyko, María-Dolores Chiara, Patricia L.M. Dahia, Rodrigo A. Toledo","doi":"10.1158/2159-8290.cd-24-0943","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0943","url":null,"abstract":"This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"25 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805772","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 : 2025-04-02DOI: 10.1158/2159-8290.CD-25-0282
Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Gemma M Balmer, David Scott
{"title":"Tackling Cancer through Global Team Science.","authors":"Rebecca L Eccles, Gabriela Carreno, Lorenzo de la Rica, Gemma M Balmer, David Scott","doi":"10.1158/2159-8290.CD-25-0282","DOIUrl":"10.1158/2159-8290.CD-25-0282","url":null,"abstract":"<p><p>Here, we discuss the seven new challenges set by Cancer Grand Challenges that are currently open for creative applications. We invite the research community to assemble global, interdisciplinary teams to tackle these challenges and ultimately change the way we think about, study, prevent, and treat cancer.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"673-677"},"PeriodicalIF":29.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555839","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 : 2025-04-02DOI: 10.1158/2159-8290.cd-24-0861
Ranjini Bhattacharya, Stanislav S. Avdieiev, Anuraag Bukkuri, Christopher J. Whelan, Robert A. Gatenby, Kenneth Y. Tsai, Joel S. Brown
{"title":"The Hallmarks of Cancer as Eco-Evolutionary Processes","authors":"Ranjini Bhattacharya, Stanislav S. Avdieiev, Anuraag Bukkuri, Christopher J. Whelan, Robert A. Gatenby, Kenneth Y. Tsai, Joel S. Brown","doi":"10.1158/2159-8290.cd-24-0861","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0861","url":null,"abstract":"The “Hallmarks of Cancer” represent characteristics of neoplastic cells. Hanahan and Weinberg noted that the acquisition of these hallmarks mimics Darwinian evolution. In this study, we deconstruct the hallmarks “color wheel” into linear, parallel, and interlinked stages: cancer initiation, evolving evolvability, niche construction, adaptations for safety, and emergent phenomenon. During carcinogenesis, a cell evolves from being part of the organism into an autonomous unit subject to natural selection. The hallmark traits enable this transition, representing adaptations for survival within their tumor ecosystem. Unwinding the hallmarks color wheel and viewing them as eco-evolutionary processes provide a unifying framework for defining, understanding, and treating cancer. Significance: Viewing the hallmarks as a sequence of adaptations captures the “why” behind the “how” of the molecular changes driving cancer. This eco-evolutionary view distils the complexity of cancer progression into logical steps, providing a framework for understanding all existing and emerging hallmarks of cancer and developing therapeutic interventions.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"56 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757883","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 : 2025-04-02DOI: 10.1158/2159-8290.cd-25-0107
Ravi Bhatia
{"title":"Don’t Lose Your Nerve: Adrenergic Signaling and Bone Marrow Regeneration after Transplantation","authors":"Ravi Bhatia","doi":"10.1158/2159-8290.cd-25-0107","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0107","url":null,"abstract":"Summary: In this issue, Nishino, Hu, Kishtagari, and colleagues report that patients who receive nonselective β-blockers after allogeneic hematopoietic cell transplant exhibit delayed platelet engraftment and reduced survival. See related article by Nishino et al., p. 748","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"12 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757884","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 : 2025-04-02DOI: 10.1158/2159-8290.cd-25-0104
Takahiko Murayama, Israel Cañadas
{"title":"Loss of p53 Induces Tolerance to Viral Mimicry as a Mechanism of Immune Evasion in Early Tumorigenesis","authors":"Takahiko Murayama, Israel Cañadas","doi":"10.1158/2159-8290.cd-25-0104","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0104","url":null,"abstract":"Summary: Ishak and colleagues report that the loss of p53 disrupts constitutive heterochromatin, enabling the transcription of immunogenic repetitive elements. Unlike acute viral mimicry activation, a chronic viral mimicry response mediated by p53 loss during cancer initiation induces tolerance to cytosolic nucleic acids, ultimately diminishing cellular immunogenicity as a strategy for immune evasion. See related article by Ishak et al., p. 793","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"24 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757882","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 : 2025-04-02DOI: 10.1158/2159-8290.CD-25-0239
Edmond M Chan, Yash Chhabra, Karen O Dixon, Adam D Durbin, Anniina Färkkilä, Anand D Jeyasekharan, Zuzana Keckesova, John R Prensner, Elvin Wagenblast, Stephanie Z Xie, Di Zhao
{"title":"Insights on Future Directions in Cancer Research from the 2025 AACR NextGen Stars.","authors":"Edmond M Chan, Yash Chhabra, Karen O Dixon, Adam D Durbin, Anniina Färkkilä, Anand D Jeyasekharan, Zuzana Keckesova, John R Prensner, Elvin Wagenblast, Stephanie Z Xie, Di Zhao","doi":"10.1158/2159-8290.CD-25-0239","DOIUrl":"10.1158/2159-8290.CD-25-0239","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 4","pages":"678-684"},"PeriodicalIF":29.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762921","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 : 2025-04-02DOI: 10.1158/2159-8290.CD-25-0210
Luis A Diaz, Lewis C Cantley
{"title":"Connections across the Cancer Continuum.","authors":"Luis A Diaz, Lewis C Cantley","doi":"10.1158/2159-8290.CD-25-0210","DOIUrl":"10.1158/2159-8290.CD-25-0210","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 4","pages":"663"},"PeriodicalIF":33.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762917","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}
Cancer discoveryPub Date : 2025-04-02DOI: 10.1158/2159-8290.CD-25-0298
Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M Vaz, Giuseppe Tarantino, Tenna Holgersen Bryde, Vindhya Vijay, Ashwin V Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D Gordan, Krushna C Patra, Vanessa S Silveira, Robert T Manguso, Marc N Wein, Christopher J Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S Gujral, Nabeel Bardeesy
{"title":"Correction: DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming.","authors":"Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M Vaz, Giuseppe Tarantino, Tenna Holgersen Bryde, Vindhya Vijay, Ashwin V Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D Gordan, Krushna C Patra, Vanessa S Silveira, Robert T Manguso, Marc N Wein, Christopher J Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S Gujral, Nabeel Bardeesy","doi":"10.1158/2159-8290.CD-25-0298","DOIUrl":"10.1158/2159-8290.CD-25-0298","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 4","pages":"862"},"PeriodicalIF":29.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762919","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}
Cancer discoveryPub Date : 2025-04-01DOI: 10.1158/2159-8290.CD-24-1509
Marina N Sharifi, Jamie M Sperger, Amy K Taylor, Katharine E Tippins, Shannon R Reese, Viridiana Carreno, Katherine R Kaufmann, Alex H Chang, Luke A Nunamaker, Charlotte Linebarger, Leilani Mora-Rodriguez, Jennifer L Schehr, Hannah M Krause, Kyle T Helzer, Matthew L Bootsma, Grace C Blitzer, John M Floberg, Christos E Kyriakopoulos, Hamid Emamekhoo, Elisabeth I Heath, Meghan Wells, Scott T Tagawa, Martin Sjöström, Atish D Choudhury, Menggang Yu, Andrew J Armstrong, Dana E Rathkopf, Himisha Beltran, Peter S Nelson, Felix Y Feng, Scott M Dehm, David Kosoff, Xiao X Wei, Rana R McKay, Shuang G Zhao, Joshua M Lang
{"title":"High-Purity CTC RNA Sequencing Identifies Prostate Cancer Lineage Phenotypes Prognostic for Clinical Outcomes.","authors":"Marina N Sharifi, Jamie M Sperger, Amy K Taylor, Katharine E Tippins, Shannon R Reese, Viridiana Carreno, Katherine R Kaufmann, Alex H Chang, Luke A Nunamaker, Charlotte Linebarger, Leilani Mora-Rodriguez, Jennifer L Schehr, Hannah M Krause, Kyle T Helzer, Matthew L Bootsma, Grace C Blitzer, John M Floberg, Christos E Kyriakopoulos, Hamid Emamekhoo, Elisabeth I Heath, Meghan Wells, Scott T Tagawa, Martin Sjöström, Atish D Choudhury, Menggang Yu, Andrew J Armstrong, Dana E Rathkopf, Himisha Beltran, Peter S Nelson, Felix Y Feng, Scott M Dehm, David Kosoff, Xiao X Wei, Rana R McKay, Shuang G Zhao, Joshua M Lang","doi":"10.1158/2159-8290.CD-24-1509","DOIUrl":"10.1158/2159-8290.CD-24-1509","url":null,"abstract":"<p><strong>Significance: </strong>Treatment resistance remains a universal driver of lethal metastatic prostate cancer, associated with acquired genomic alterations and lineage transitions. Using a novel high-purity CTC isolation approach for CTC transcriptional profiling, we identified four lineage phenotypes differentially associated with prognosis in metastatic prostate cancer.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1-OF19"},"PeriodicalIF":33.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751257","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}