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. The cellular origin and developmental trajectory of DICER1 syndrome-associated tumors are currently unknown. Here, the authors employ a lineage-traceable genetically modified mouse model for DICER1 syndrome to identify universal fibroblasts as the likely cellular origin of mouse Dicer1 sarcoma and map their developmental trajectory, findings that are validated in human DICER1 mesenchymal tumors.
Kommoss et al. (Mon,) studied this question.
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