Caitlin A. McIntyre, Adrien Grimont, Jiwoon Park, Yinuo Meng, Whitney J. Sisso, Kenneth Seier, Gun Ho Jang, Henry Walch, Victoria G. Aveson, David J. Falvo, William B. Fall, Christopher W. Chan, Andrew Wenger, Brett L. Ecker, Alessandra Pulvirenti, Rebecca Gelfer, Maria Paz Zafra, Nikolaus Schultz, Wungki Park, Eileen M. O’Reilly, Rohit Chandwani
{"title":"人类胰腺癌中特定 KRAS 突变体的不同临床结果和生物学特征","authors":"Caitlin A. McIntyre, Adrien Grimont, Jiwoon Park, Yinuo Meng, Whitney J. Sisso, Kenneth Seier, Gun Ho Jang, Henry Walch, Victoria G. Aveson, David J. Falvo, William B. Fall, Christopher W. Chan, Andrew Wenger, Brett L. Ecker, Alessandra Pulvirenti, Rebecca Gelfer, Maria Paz Zafra, Nikolaus Schultz, Wungki Park, Eileen M. O’Reilly, Rohit Chandwani","doi":"10.1016/j.ccell.2024.08.002","DOIUrl":null,"url":null,"abstract":"<p><em>KRAS</em> mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that <em>KRAS</em><sup><em>G12R</em></sup> mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. <em>KRAS</em><sup><em>G12R</em></sup> tumors are associated with decreased distant recurrence and improved survival as compared to <em>KRAS</em><sup><em>G12D</em></sup>. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in <em>KRAS</em><sup><em>G12D</em></sup> and increased nuclear factor κB (NF-κB) signaling in <em>KRAS</em><sup><em>G12R</em></sup> tumors. Orthogonal studies of mouse <em>Kras</em><sup><em>G12R</em></sup> PDAC organoids show decreased migration and improved survival in orthotopic models. <em>KRAS</em> alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":48.8000,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer\",\"authors\":\"Caitlin A. McIntyre, Adrien Grimont, Jiwoon Park, Yinuo Meng, Whitney J. Sisso, Kenneth Seier, Gun Ho Jang, Henry Walch, Victoria G. Aveson, David J. Falvo, William B. Fall, Christopher W. Chan, Andrew Wenger, Brett L. Ecker, Alessandra Pulvirenti, Rebecca Gelfer, Maria Paz Zafra, Nikolaus Schultz, Wungki Park, Eileen M. O’Reilly, Rohit Chandwani\",\"doi\":\"10.1016/j.ccell.2024.08.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><em>KRAS</em> mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that <em>KRAS</em><sup><em>G12R</em></sup> mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. <em>KRAS</em><sup><em>G12R</em></sup> tumors are associated with decreased distant recurrence and improved survival as compared to <em>KRAS</em><sup><em>G12D</em></sup>. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in <em>KRAS</em><sup><em>G12D</em></sup> and increased nuclear factor κB (NF-κB) signaling in <em>KRAS</em><sup><em>G12R</em></sup> tumors. Orthogonal studies of mouse <em>Kras</em><sup><em>G12R</em></sup> PDAC organoids show decreased migration and improved survival in orthotopic models. <em>KRAS</em> alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.</p>\",\"PeriodicalId\":9670,\"journal\":{\"name\":\"Cancer Cell\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":48.8000,\"publicationDate\":\"2024-08-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Cell\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ccell.2024.08.002\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2024.08.002","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer
KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.
期刊介绍:
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.