Cancer discovery最新文献

{"title":"A Guide to Extrachromosomal DNA: Cancer’s Dynamic Circular Genome","authors":"Natasha E. Weiser, Thomas B.K. Watkins, Howard Y. Chang, Paul S. Mischel","doi":"10.1158/2159-8290.cd-25-0230","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0230","url":null,"abstract":"Focal amplifications of oncogenes are important cancer drivers. They can occur on chromosomes or in the context of circular extrachromosomal DNA (ecDNA). Many key features of ecDNAs were described in the 1960s to 1980s, including their “unstable” nature and their ability to confer drug resistance. With the benefit of new technologies, our understanding of ecDNAs has advanced dramatically in the last decade, both in breadth and in depth, including the remarkable discovery that ecDNAs are present in 17% of all cancers and are associated with worse patient outcomes. In this study, we present a guide to ecDNA tools and biology. Significance: Focal amplifications on ecDNAs are commonly found in cancer and are associated with poor patient outcomes and distinct biology. In this review, we provide a guide to ecDNA biology and available tools as well as our perspective on this rapidly evolving field.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"32 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880661","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":"The Future of Personalized Cancer Vaccines","authors":"Dylan J. Martini, Catherine J. Wu","doi":"10.1158/2159-8290.cd-25-0300","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0300","url":null,"abstract":"In early clinical studies, genomics-guided personalized cancer vaccines (PCVs) have demonstrated the capabilities of inducing long-term, tumor-specific immune responses across various malignancies, clinical settings, and treatment regimens. Now that PCVs have advanced to large-scale, randomized clinical trials, we are at a pivotal time. The future success of PCVs will likely be dictated by our collective ability to apply and iterate upon the foundational lessons from early and ongoing in-depth studies so that we can rationally exploit the cytolytic capabilities of PCVs to eradicate advanced cancer, cure patients in the adjuvant setting, and prevent the development of malignancy in high-risk patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"23 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880660","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":"Intrinsic properties of the lymph node render it immunologically susceptible to metastasis","authors":"Benjamin M. Kahn, Raymond W.S. Ng, Il-Kyu Kim, Cody Eskandarian, Chelsey O. Chen, Bing Huang, Alfredo Lucas, Lequn Li, Ivan Maillard, Ben Z. Stanger","doi":"10.1158/2159-8290.cd-24-1847","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1847","url":null,"abstract":"Lymph nodes (LNs) are the staging grounds for anti-tumor immunity, therefore their high susceptibility to metastatic colonization is a paradox. Previous studies have suggested that extrinsic tumor-derived factors precondition the draining LN to enable tumor cell survival by promoting a state of immune suppression. Here, we investigate whether properties of the LN itself may impede its ability to clear metastasizing tumor cells. Using multiple immunocompetent transplant models, we show that LNs possess intrinsic features, independent of preconditioning, which make them an advantageous site for tumor cells to evade T cell control. Tumor growth in the LN is facilitated by regulatory T cells, which locally suppress the cytolytic capacity of tumor-specific CD8 T cells by restricting IL-2. These findings identify an intrinsic mechanism that contributes to the high rate of LN metastasis in solid tumors.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"32 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867023","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":"Depletion of effector regulatory T cells associates with major response to induction dual immune checkpoint blockade.","authors":"Xianli Jiang,Nils-Petter Rudqvist,Bo Jiang,Shengbin Ye,Shan He,Qingnan Liang,Jinzhuang Dou,Michelle D Williams,Joe Dan Dunn,Jason M Johnson,Keiko Akagi,Weihong Xiao,Shaoheng Liang,Satvik Elayavalli,Baohua Sun,Edwin R Parra,Renata Ferrarotto,Adam S Garden,Clifton David Fuller,Jay Reddy,Neil D Gross,Miriam N Lango,Cheuk Hong Leung,Suyu Liu,Diane D Liu,Meng Li,J Jack Lee,Michael A Curran,Jack Phan,Ken Chen,Maura L Gillison","doi":"10.1158/2159-8290.cd-24-1390","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1390","url":null,"abstract":"In a phase 2 trial, local-regionally advanced HPV-positive oropharyngeal carcinoma patients (N = 35) received ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy (NCT03799445). Co-primary endpoints included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histopathologic response rate. Single-cell profiling revealed responders had higher baseline intratumoral CD8+ T cells with a tumor-reactive, tissue-resident memory (TRM) phenotype and a treatment-related decrease in effector regulatory T (eTreg) cells. The eTreg decrease correlated with CD8+ T-cell clonotype transitioning from TRM to effector memory and IFNG+ effector cells. In nonresponders, clonotypes transitioned to exhausted TRM and proliferating cells. Multivariable regression modeling determined the baseline feature most associated with reduction in tumor viability was the proportion of FCGR3A-expressing NK cells, which are capable of ipilimumab-dependent depletion of CTLA4high eTregs. eTreg depletion may be critical for major response to induction dual immune checkpoint blockade.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849504","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":"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}

{"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}

{"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}

{"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}

{"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}

{"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}