Mechanistic dissection and targeting non-cell autonomous tumor promotion in DICER1 cancer predisposition

/ABSTRACT DICER1 is a ribonuclease III enzyme essential for processing precursor microRNAs into mature microRNAs that regulate gene expression. Germline heterozygous loss of function mutations in DICER1 cause a cancer predisposition characterized by rare pediatric tumors such as pleuropulmonary blastoma and fusion negative rhabdomyosarcoma (FN RMS). Despite clear clinical relevance, the mechanism by which loss of a single DICER1 allele promotes tumorigenesis in humans remains unknown. Most tumors arising in DICER1 cancer predisposition acquire secondary somatic mutations in the RNase IIIb domain that selectively impair 5p microRNA processing, leading to a global imbalance in microRNA populations. How this imbalance contributes to cancer development and progression is poorly understood. The human relevance of this work lies in addressing a fundamental gap in understanding DICER1 cancer predisposition, which impacts pediatric patients with limited therapeutic options. Identifying non–cell autonomous mechanisms of tumor promotion will inform development of novel, targeted therapies that may benefit patients with DICER1-associated tumors and potentially broader cancers with altered microRNA processing. Our long-term goal is to elucidate the mechanisms of cancer predisposition and tumorigenesis in DICER1 cancer predisposition. Our objective of this proposal is to define the molecular and microenvironmental mechanisms underlying DICER1 haploinsufficiency using a well characterized FN RMS mouse model that faithfully recapitulates key genetic and biological features of human disease. Murine models are essential for this work because they enable controlled manipulation of Dicer1 dosage in specific cell populations within an intact immune system, allowing interrogation of tumor–stromal interactions that cannot be modeled in vitro or in human subjects. Genetically engineered mice allow temporal and cell type–specific modulation of neutrophils and neutrophil extracellular traps (NETs), providing mechanistic insight into immune mediated tumor promotion. We will (1) define the role of neutrophils and NET formation in mediating DICER1 haploinsufficiency and (2) evaluate therapeutic inhibition of NET release as a strategy to suppress tumor growth. These studies will identify actionable pathways, including PADI4 dependent NET formation, and establish a foundation for translating NET targeted therapies into clinical approaches for DICER1 syndrome and related malignancies. Collectively, this work will elucidate fundamental mechanisms of cancer predisposition, bridge murine findings to human disease, and identify novel therapeutic targets with direct clinical relevance. Project Number: 1R01CA311986-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Mark Hatley | Institution: ST. JUDE CHILDREN'S RESEARCH HOSPITAL, MEMPHIS, TN | Award Amount: $628,073 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 BTC-Y (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11340096