Spatial & single cell transcriptomic analysis of a lineage-traceable mouse model of DICER1 Syndrome informs tumor developmental hierarchy

DICER1 syndrome predisposes children and young adults to tumor development across various organs. Most of these cancers are sarcomas, which uniquely express the RNase IIIb domain-deficient form of DICER1 and exhibit histological and molecular similarities regardless of their anatomical origins. To uncover their cellular origin and developmental hierarchy, we established a lineage-traceable genetically engineered mouse model allowing for controlled activation of Dicer1 mutations in Hic1+ mesenchymal stromal cells. This resulted in the development of renal tumors closely mirroring human DICER1 sarcoma histologically and molecularly. Spatial single-cell transcriptomics analysis revealed that a Hic1+Pdgfra+Mfap4+ fibroblastic progenitor population, corresponding to perivascular universal fibroblasts of steady-state kidneys, exhibits the capability to undergo rhabdomyoblastic differentiation or transition into proliferative sarcomatous cells. Investigation of patient samples identified analogous cell states and developmental trajectories. This study uncovers a fibroblastic origin for DICER1 sarcoma and provides a faithful model for future mechanistic and translational investigation.