Spatial single cell transcriptomic analysis of a lineage-traceable mouse model of DICER1 Syndrome informs tumor developmental hierarchy [scRNA-seq]

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.