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Non-cell-autonomous tumor promotion in DICER1 cancer predisposition
Randolph K Larsen1, Jason A Hanna2, Hongjian Jin3
1St. Jude Graduate School of Biomedical Sciences, Memphis, TN, USA.
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.
Insights
Germline DICER1 mutations promote tumor growth by altering neutrophil function and increasing neutrophil extracellular traps (NETs). Targeting neutrophils or NETs may reduce cancer risk in individuals with DICER1 mutations.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- DICER1-related tumors arise from germline DICER1 loss-of-function mutations (DICER1+/-) and a somatic second hit.
- The role of the germline DICER1+/- mutation in initiating tumorigenesis remains unclear.
Purpose of the Study:
- To investigate the role of germline DICER1 haploinsufficiency in promoting tumor formation.
- To explore the involvement of neutrophils and neutrophil extracellular traps (NETs) in DICER1-related tumorigenesis.
Main Methods:
- Utilized spontaneous and allograft mouse models of rhabdomyosarcoma with germline and conditional Dicer1 heterozygous deletion.
- Analyzed tumor composition for neutrophil infiltration and measured circulating NETs.
- Employed genetic and pharmacological strategies to inhibit NET release.
Main Results:
- Germline Dicer1 deletion accelerated tumor development and increased penetrance, unlike conditional deletion in tumor cells.
- DICER1+/- tumors showed enrichment of neutrophils, and tumor-bearing mice exhibited increased NETs.
- Inhibition of NET release significantly reduced tumor promotion in DICER1+/- mice.
Conclusions:
- Germline DICER1 haploinsufficiency promotes rhabdomyosarcoma development through non-cell-autonomous mechanisms involving neutrophils.
- Neutrophils and NETs play a crucial role in promoting tumor growth in DICER1+/- contexts.
- Targeting neutrophils or NETs presents a potential therapeutic strategy to mitigate cancer risk in individuals with germline DICER1 mutations.
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