Intended Audience
Natural Science and Mathematics Colloquium
Targeting the tumor microenvironment in pediatric cancer
Randolph Larsen IV '19
St. Jude Children’s Research Hospital
Wednesday, September 25, 2024
Schaefer Hall 106 – 4:45 pm
DICER1 syndrome is a cancer predisposition syndrome where affected patients have increased risk of neoplasms including pleuropulmonary blastoma, Sertoli-Leydig cell tumor, and rhabdomyosarcoma (RMS). This syndrome is defined by germline heterozygous loss of function mutations in the gene DICER1, but it remains unclear exactly how these mutations predispose children to develop cancer. Whether DICER1+/- variants participate in tumorigenesis or simply provide a sensitized background for acquisition of second hit mutations is unknown. We show that germline heterozygous loss of Dicer1 promotes tumor formation via aberrant neutrophil function in an RMS mouse model. Germline heterozygous deletion of Dicer1 decreased tumor latency and increased tumor penetrance while conditional heterozygous deletion in tumor cells did not, illustrating contributions from the tumor microenvironment were required for tumor promotion. We show Dicer1+/- murine and human tumors were enriched for neutrophils and tumor-bearing mice had abundant circulating neutrophil extracellular traps (NETs). Genetically abrogating NET-release increased tumor latency and decreased penetrance, suggesting NETs promote tumor growth. These findings demonstrate that DICER1+/- mutations promote tumor growth and suggest targeting neutrophils/NET-release may reduce cancer risk in DICER1+/- individuals.
This event is free and open to the public. It is meant for a general audience. If you are an instructor, please announce it to your students.