Cancer discovery最新文献

{"title":"Hidden in Plain Sight: Clinical Imaging of the Tumor Microenvironment with PET.","authors":"Timothy H Witney","doi":"10.1158/2159-8290.CD-24-1673","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1673","url":null,"abstract":"<p><p>PET imaging enables the spatiotemporal assessment of tumor biomarkers. In this issue, Kong and colleagues describe the clinical PET imaging of tumor-associated fibroblasts, which improved the diagnostic accuracy and management of a subset of patients with medullary thyroid carcinoma. See related article by Kong et al., p. 316.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 2","pages":"264-266"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363593","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":"Strengthening Asian/Asian American, Native Hawaiian, and Pacific Islander Leadership in Cancer Research.","authors":"Lawrence W Wu, Ryan H Moy","doi":"10.1158/2159-8290.CD-24-1618","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1618","url":null,"abstract":"<p><p>Individuals in the United States from Asian and Asian American, Native Hawaiian, and Pacific Islander (AANHPI) backgrounds face a distinct set of cancer-related disparities. In this study, in conjunction with the American Association for Cancer Research Asian/AANHPI Task Force, we highlight the unique disparities faced by AANHPI patients and professionals, and we offer actionable recommendations on how to strengthen AANHPI leadership in cancer research.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 2","pages":"267-270"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363598","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":"Predisposition Footprints in the Somatic Genome of Wilms Tumors.","authors":"Taryn D Treger, Jenny Wegert, Anna Wenger, Tim H H Coorens, Reem Al-Saadi, Paul G Kemps, Jonathan Kennedy, Conor Parks, Nathaniel D Anderson, Angus Hodder, Aleksandra Letunovska, Hyunchul Jung, Toochi Ogbonnah, Mi K Trinh, Henry Lee-Six, Guillaume Morcrette, Marry M van den Heuvel-Eibrink, Jarno Drost, Ruben van Boxtel, Eline J M Bertrums, Bianca F Goemans, Evangelia Antoniou, Dirk Reinhardt, Heike Streitenberger, Barbara Ziegler, Jack Bartram, John C Hutchinson, Gordan M Vujanic, Christian Vokuhl, Tanzina Chowdhury, Rhoikos Furtwängler, Norbert Graf, Kathy Pritchard-Jones, Manfred Gessler, Sam Behjati","doi":"10.1158/2159-8290.CD-24-0878","DOIUrl":"10.1158/2159-8290.CD-24-0878","url":null,"abstract":"<p><p>Approximately 10% of children with cancer harbor a mutation in a predisposition gene. In children with the kidney cancer Wilms tumor, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumorigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumor, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukemias), utilizing whole-genome sequencing, RNA sequencing, and genome-wide methylation, validating our findings in an independent cohort. Tumor development differed in children harboring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high-risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumorigenesis, suggesting a variant-specific approach to managing children merits consideration. Significance: Tumors that arise in children with a cancer predisposition may develop through the same mutational pathways as sporadic tumors. We examined this question in the childhood kidney cancer, Wilms tumor. We found that certain predispositions dictate the genetic development of tumors, with clinical implications for these children. See related commentary by Brzezinski and Malkin, p. 258.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"286-298"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812194","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}

{"title":"Stromal KITL/SCF maintains pancreas tissue homeostasis and restrains tumor progression","authors":"M. Kathrina. Oñate, Chet Oon, Sohinee Bhattacharyya, Vivien Low, Canping Chen, Xiaofan Zhao, Frank Arnold, Ziqiao Yan, Sneha Pramod, Yan Hang, Yu-Jui Ho, Scott W. Lowe, Seung K. Kim, Zheng Xia, Mara H. Sherman","doi":"10.1158/2159-8290.cd-24-1079","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1079","url":null,"abstract":"Components of normal tissue architecture serve as barriers to tumor progression. Inflammatory and wound-healing programs are requisite features of solid tumorigenesis, wherein alterations to immune and non-immune stromal elements enable loss of homeostasis during tumor onset. The precise mechanisms by which normal stromal cell states limit tissue plasticity and tumorigenesis, and which are lost during tumor progression, remain largely unknown. Here we show that healthy pancreatic mesenchyme expresses the paracrine signaling molecule KITL, also known as stem cell factor, and identify loss of stromal KITL during tumorigenesis as tumor-promoting. Genetic inhibition of mesenchymal KITL in the contexts of health, injury, and cancer together indicate a role for KITL signaling in maintenance of pancreas tissue architecture, such that loss of the stromal KITL pool increased tumor growth and reduced survival of tumor-bearing mice. Together, these findings implicate loss of mesenchymal KITL as a mechanism for establishing a tumor-permissive microenvironment.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"60 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258398","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":"Tumor-Intrinsic Kinome Landscape of Pancreatic Cancer Reveals New Therapeutic Approaches.","authors":"Yi Xu, Xianlu L Peng, Michael P East, Ian C McCabe, Grace C Stroman, Madison R Jenner, Priscilla S Chan, Ashley B Morrison, Emily C Shen, Silvia G Hererra, Chinmaya U Joisa, Naim U Rashid, Alina C Iuga, Shawn M Gomez, Lisa Miller-Phillips, Stefan Boeck, Volker Heinemann, Michael Haas, Steffen Ormanns, Gary L Johnson, Jen Jen Yeh","doi":"10.1158/2159-8290.CD-23-1480","DOIUrl":"10.1158/2159-8290.CD-23-1480","url":null,"abstract":"<p><strong>Significance: </strong>We provide a comprehensive tumor-intrinsic kinome landscape that provides a roadmap for the use of kinase inhibitors in PDAC treatment approaches.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"346-362"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779338","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}

{"title":"CTR-FAPI PET Enables Precision Management of Medullary Thyroid Carcinoma.","authors":"Ziren Kong, Zhu Li, Xi-Yang Cui, Jian Wang, Mengxin Xu, Yang Liu, Junyi Chen, Song Ni, Zongmin Zhang, Xiaowei Fan, Jiazhao Huang, Yansong Lin, Yuning Sun, Yuqin He, Xinfeng Lin, Tianyu Meng, Han Li, Yixuan Song, Boshizhang Peng, Changming An, Chenyan Gao, Nan Li, Chen Liu, Yiming Zhu, Zhi Yang, Zhibo Liu, Shaoyan Liu","doi":"10.1158/2159-8290.CD-24-0897","DOIUrl":"10.1158/2159-8290.CD-24-0897","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but current clinical practice fails to localize the disease in 29% to 60% of patients. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]fluorodeoxyglucose ([18F]FDG) PET-CT in 50 patients with MTC. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, P = 0.0002). This improved detection was attributed to increased tumor uptake (maximum standardized uptake value = 11.71 ± 9.16 vs. 2.55 ± 1.73, P < 0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared with [18F]FDG (96.7% vs. 43.3%, P < 0.0001). Notably, the management of 32% of patients was altered following [68Ga]Ga-CTR-FAPI PET-CT, and the surgical plan was changed for 66.7% of patients. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared with [18F]FDG PET-CT, enabling precision management of patients with MTC. Significance: In this first-in-class clinical trial of CTR, [68Ga]Ga-CTR-FAPI demonstrated an improved patient-based detection rate (98%), tumor uptake (maximum standardized uptake value = 11.71 ± 9.16), and pathology-validated diagnostic accuracy (96.7%) compared with the currently approved method in MTC treatment. It directly altered management in 32% of patients, enabling precision diagnosis and management of MTC. See related commentary by Witney, p. 264.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"316-328"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521077","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}

{"title":"Knudson's \"Two-Hit\" Hypothesis and Cancer Predisposition: A Bit More Complicated but Still Going Strong.","authors":"Jack J Brzezinski, David Malkin","doi":"10.1158/2159-8290.CD-24-1662","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-1662","url":null,"abstract":"<p><p>This study by Treger and colleagues is a comprehensive evaluation of the genome and epigenome of tumors and constitutional tissue from children with Wilms tumor predisposition syndromes that demonstrates that the molecular features of Wilms tumors are dependent on the constitutional milieu of the patient in which they develop. See related article by Treger et al., p. 286.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"15 2","pages":"258-260"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363595","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":"LINE-1 ORF1p Mimics Viral Innate Immune Evasion Mechanisms in Pancreatic Ductal Adenocarcinoma","authors":"Eunae You, Bidish K. Patel, Alexandra S. Rojas, Siyu Sun, Patrick Danaher, Natalie I. Ho, Ildiko E. Phillips, Michael J. Raabe, Yuhui Song, Katherine H. Xu, Joshua R. Kocher, Peter M. Richieri, Phoebe Shin, Martin S. Taylor, Linda T. Nieman, Benjamin D. Greenbaum, David T. Ting","doi":"10.1158/2159-8290.cd-24-1317","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1317","url":null,"abstract":"Repeat element viral mimicry is a common feature in pancreatic ductal adenocarcinoma (PDAC) that require mechanisms to manage this repeat “viral” load and attenuate innate immune responses. Here, we show that the LINE-1 ORF1 protein (ORF1p) in PDAC cells plays a role in shielding repeat RNAs from activating a pathogen recognition receptor (PRR)-mediated antiviral response that is independent of retrotransposition. Suppression of ORF1p using short hairpin RNA induces innate immune responses through the dsRNA sensors RIG-I and MAVS. Low ORF1p PDAC cell lines have suppressed expression of PRRs demonstrating convergent mechanisms to suppress innate immune signaling. Localization of ORF1p in processing bodies (PBs) with the dsRNA helicase MOV10 were found important for these antiviral responses. Loss of ORF1p resulted in significant growth reduction in tumorspheres and mouse xenografts with an enriched epithelial cell state, and high ORF1p expression was associated with worsened survival in a cohort of human PDAC patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"47 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367368","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":"Copper Drives Remodeling of Metabolic State and Progression of Clear Cell Renal Cell Carcinoma.","authors":"Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jahnavi Venkat, Vanina Toffessi Tcheuyap, Jacek Biesiada, Catherine A Behrmann, Katherine E Vest, James Brugarolas, Pier Paolo Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, John T Cunningham, Maria F Czyzyk-Krzeska","doi":"10.1158/2159-8290.CD-24-0187","DOIUrl":"10.1158/2159-8290.CD-24-0187","url":null,"abstract":"<p><strong>Significance: </strong>The work establishes a requirement for glucose-dependent coordination between energy production and redox homeostasis, which is fundamental for the survival of cancer cells that accumulate Cu and contributes to tumor growth.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"401-426"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543875","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}

{"title":"Glioblastoma Cortical Organoids Recapitulate Cell-State Heterogeneity and Intercellular Transfer.","authors":"Vamsi Mangena, Rony Chanoch-Myers, Rafaela Sartore, Bruna Paulsen, Simon Gritsch, Hannah Weisman, Toshiro Hara, Xandra O Breakefield, Koen Breyne, Aviv Regev, Kwanghun Chung, Paola Arlotta, Itay Tirosh, Mario L Suvà","doi":"10.1158/2159-8290.CD-23-1336","DOIUrl":"10.1158/2159-8290.CD-23-1336","url":null,"abstract":"<p><p>Glioblastoma (GBM) is characterized by heterogeneous malignant cells that are functionally integrated within the neuroglial microenvironment. In this study, we model this ecosystem by growing GBM into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex. Single-cell RNA sequencing analysis suggests that, compared with matched gliomasphere models, GBM cortical organoids more faithfully recapitulate the diversity and expression programs of malignant cell states found in patient tumors. Additionally, we observe widespread transfer of GBM transcripts and GFP to nonmalignant cells in the organoids. Mechanistically, this transfer involves extracellular vesicles and is biased toward defined GBM cell states and astroglia cell types. These results extend previous GBM organoid modeling efforts and suggest widespread intercellular transfer in the GBM neuroglial microenvironment. Significance: Models that recapitulate intercellular communications in GBM are limited. In this study, we leverage GBM cortical organoids to characterize widespread mRNA and GFP transfer from malignant to nonmalignant cells in the GBM neuroglial microenvironment. This transfer involves extracellular vesicles, may contribute to reprogramming the microenvironment, and may extend to other cancer types. See related commentary by Shakya et al., p. 261.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"299-315"},"PeriodicalIF":29.7,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380088","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}