Abstract A044: Dissecting the developmental trajectory of DICER1 syndrome-associated sarcoma with genetically engineered mouse models
DICER1 syndrome, also known as DICER1-related tumor predisposition, encompasses a spectrum of malignancies mainly in children and young adults, affecting lung, gynecologic tract, kidney and other organs. Most of these tumors are sarcomas, exhibiting histological and molecular similarities regardless of their anatomical origins, and only express the RNase IIIb domain-defective DICER1. These unique mode of biallelic mutation of DICER1 leads to systemic loss of 5p-miRNAs, but not 3p-miRNAs, and subsequent transcriptional reprogramming. To uncover their cellular origin and developmental hierarchy, we establish a lineage-traceable genetically engineered mouse model (GEMM) with CreERT2 controlled activation of hemizygous Dicer1 RNase IIIb mutation in Hic1+ mesenchymal stromal cells that are widely present in various organs. Surprisingly, activation of Dicer1 mutations in juvenile mice leads to tumor development restricted to the kidneys. These tumors closely mirrored the developmental continuum of human DICER1 syndrome-associated sarcoma histologically and molecularly, including the accumulation of p53 and Kras mutations in high-grade tumors. Spatial single-cell transcriptomic analysis reveals a Hic1+Pdgfra+Dpt+Pi16+ fibroblastic progenitor population, corresponding to universal fibroblasts subjacent to transitional epithelium of renal collecting ducts, that can undergo rhabdomyoblastic differentiation or become proliferative high-grade sarcomatous cells. Supporting this, deletion of p53 in this Dicer1 RNase IIIb-mutant GEMM led to the development of ubiquitously high-grade renal sarcoma. Investigation of patient samples identifies analogous cell states and developmental trajectories. Lastly, we identified that the MAPK pathway is activated along the progression of both mouse and human tumors. Dicer1 GEMM – derived sarcoma cells are highly sensitive to MAPK inhibition by a MEK2 inhibitor, trametinib, regardless of their KRAS mutation status. Thus, our study uncovers a fibroblastic origin for DICER1 syndrome-associated sarcoma and provides a faithful mouse model for future mechanistic and translational investigation. Felix Kommoss, Joyce Yu-Han Zhang, Branden Lynch, Shary Yuting Chen, Lesley Ann. Hill, Janine Senz, Emma Jingjie Guo, Grace Longyijie Wei, Michael Underhill, Huntsman David, Yemin Wang. Dissecting the developmental trajectory of DICER1 syndrome-associated sarcoma with genetically engineered mouse models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A044.