Spatial single cell transcriptomic analysis informs tumor developmental hierarchy of DICER1 syndrome related sarcoma

DICER1-related tumor predisposition (DRTP), also known as DICER1 syndrome, encompasses a spectrum of malignancies mainly in children and young adults. Most are sarcomas, exhibiting histological and molecular similarities regardless of their anatomical origins, and only express the RNase IIIb domain-defective DICER1. To uncover their cellular origin and developmental hierarchy, we establish a lineage-traceable genetically engineered mouse model with controlled activation of hemizygous Dicer1 RNase IIIb mutation in Hic1⁺ mesenchymal stromal cells. This causes renal tumors closely mirroring the developmental continuum of human DRTP sarcoma histologically and molecularly. 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 sarcomatous cells. Investigation of patient samples identifies analogous cell states and developmental trajectories. This study uncovers a fibroblastic origin for DRTP sarcoma and provides a faithful mouse model for future mechanistic and translational investigation.