Non-cell-autonomous tumor promotion in DICER1 cancer predisposition
DICER1-related tumors are characterized by germline loss-of-function mutations in one DICER1 allele (DICER1<sup>+/-</sup>) and a somatic "second hit" mutation in the remaining DICER1 allele. Whether the germline DICER1<sup>+/-</sup> 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<sup>+/-</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 Dicer1<sup>+/-</sup> mice, suggesting NETs promote tumor growth. These findings demonstrate that germline DICER1<sup>+/-</sup> mutations promote tumor growth and suggest that targeting neutrophils/NET release may reduce cancer risk in DICER1<sup>+/-</sup> individuals.
Authors
- Catherine J. Drummond (ORCID: https://orcid.org/0000-0002-7019-3173)
- Patrick Schreiner (ORCID: https://orcid.org/0000-0001-5391-2642)
- Jason W. Rosch (ORCID: https://orcid.org/0000-0002-1798-1760)
- Jerold E. Rehg (ORCID: https://orcid.org/0000-0002-7184-6332)
- Myron K. Evans (ORCID: https://orcid.org/0000-0002-7678-5815)
- Kristin Wiggins (ORCID: https://orcid.org/0000-0002-9764-3349)
- Jason A. Hanna (ORCID: https://orcid.org/0000-0001-7253-7964)
- Casey G. Langdon (ORCID: https://orcid.org/0000-0002-0010-7209)
- Matthew R. Garcia
- Amy Iverson (ORCID: https://orcid.org/0000-0001-8039-1053)
- Jongchan Hwang
- Kris Ann P. Schultz (ORCID: https://orcid.org/0000-0002-1788-5832)
- Grace E. Adkins
- Kyna Vuong
- Mark E. Hatley (ORCID: https://orcid.org/0000-0001-7147-3946)
- David Finkelstein (ORCID: https://orcid.org/0000-0002-5196-6556)
- Hongjian Jin (ORCID: https://orcid.org/0000-0003-3833-7170)
- Bradley T. Stevens
- Kristin B. Reed (ORCID: https://orcid.org/0000-0003-0595-9096)
- Darden W. Kimbrough
- Randolph K. Larsen (ORCID: https://orcid.org/0000-0003-0727-0049)
- Jack D. Hopkins
Institutions
- St. Jude Children's Research Hospital (US)
- Children’s Minnesota - St. Paul Hospital (US)
Publication Details
- Journal
- Developmental Cell
- Published
- 2025-10-01
- DOI
- https://doi.org/10.1016/j.devcel.2025.09.001
- Primary Topic
- Congenital Diaphragmatic Hernia Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00