Randolph K. Larsen, Jason A. Hanna, Hongjian Jin, Kristin B. Reed, Darden W. Kimbrough, Kyna Vuong, Jongchan Hwang, Grace E. Adkins, Jack D. Hopkins, Bradley T. Stevens, Myron K. Evans, Casey G. Langdon, Catherine J. Drummond, Matthew R. Garcia, Kristin B. Wiggins, Amy R. Iverson, David Finkelstein, Patrick A. Schreiner, Jason W. Rosch, Jerold E. Rehg, Mark E. Hatley
{"title":"Non-cell-autonomous tumor promotion in DICER1 cancer predisposition","authors":"Randolph K. Larsen, Jason A. Hanna, Hongjian Jin, Kristin B. Reed, Darden W. Kimbrough, Kyna Vuong, Jongchan Hwang, Grace E. Adkins, Jack D. Hopkins, Bradley T. Stevens, Myron K. Evans, Casey G. Langdon, Catherine J. Drummond, Matthew R. Garcia, Kristin B. Wiggins, Amy R. Iverson, David Finkelstein, Patrick A. Schreiner, Jason W. Rosch, Jerold E. Rehg, Mark E. Hatley","doi":"10.1016/j.devcel.2025.09.001","DOIUrl":null,"url":null,"abstract":"DICER1-related tumors are characterized by germline loss-of-function mutations in one <em>DICER1</em> allele (<em>DICER1</em><sup><em>+/−</em></sup>) and a somatic “second hit” mutation in the remaining <em>DICER1</em> allele. Whether the germline <em>DICER1</em><sup><em>+/−</em></sup> mutation participates in tumorigenesis is unknown. We show that germline heterozygous loss of <em>Dicer1</em> promotes tumor formation via aberrant neutrophil function in spontaneous and allograft mouse models of rhabdomyosarcoma. Germline heterozygous deletion of <em>Dicer1</em> decreased tumor latency and increased tumor penetrance, while conditional heterozygous deletion in tumor cells did not, illustrating that non-cell-autonomous contributions were required for tumor promotion. We show that <em>Dicer1</em><sup><em>+/−</em></sup> murine and human tumors were enriched for neutrophils and that tumor-bearing mice had abundant circulating neutrophil extracellular traps (NETs). Genetically and pharmacologically preventing NET release reduced tumor promotion in <em>Dicer1</em><sup><em>+/−</em></sup> mice, suggesting NETs promote tumor growth. These findings demonstrate that germline <em>DICER1</em><sup><em>+/−</em></sup> mutations promote tumor growth and suggest that targeting neutrophils/NET release may reduce cancer risk in <em>DICER1</em><sup><em>+/−</em></sup> individuals.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"118 1","pages":""},"PeriodicalIF":8.7000,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Developmental cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.devcel.2025.09.001","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
DICER1-related tumors are characterized by germline loss-of-function mutations in one DICER1 allele (DICER1+/−) and a somatic “second hit” mutation in the remaining DICER1 allele. Whether the germline DICER1+/− mutation participates in tumorigenesis is unknown. We show that germline heterozygous loss of Dicer1 promotes tumor formation via aberrant neutrophil function in spontaneous and allograft mouse models of rhabdomyosarcoma. Germline heterozygous deletion of Dicer1 decreased tumor latency and increased tumor penetrance, while conditional heterozygous deletion in tumor cells did not, illustrating that non-cell-autonomous contributions were required for tumor promotion. We show that Dicer1+/− murine and human tumors were enriched for neutrophils and that tumor-bearing mice had abundant circulating neutrophil extracellular traps (NETs). Genetically and pharmacologically preventing NET release reduced tumor promotion in Dicer1+/− mice, suggesting NETs promote tumor growth. These findings demonstrate that germline DICER1+/− mutations promote tumor growth and suggest that targeting neutrophils/NET release may reduce cancer risk in DICER1+/− individuals.
期刊介绍:
Developmental Cell, established in 2001, is a comprehensive journal that explores a wide range of topics in cell and developmental biology. Our publication encompasses work across various disciplines within biology, with a particular emphasis on investigating the intersections between cell biology, developmental biology, and other related fields. Our primary objective is to present research conducted through a cell biological perspective, addressing the essential mechanisms governing cell function, cellular interactions, and responses to the environment. Moreover, we focus on understanding the collective behavior of cells, culminating in the formation of tissues, organs, and whole organisms, while also investigating the consequences of any malfunctions in these intricate processes.