Spatial single cell transcriptomic analysis of a novel DICER1 Syndrome GEMM informs the cellular origin and developmental hierarchy of associated sarcomas

DICER1 syndrome predisposes children and young adults to tumor development across various organs. Many of these cancers are sarcomas, which uniquely express the RNase IIIb domain-deficient form of DICER1 and exhibit consistent 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 that allows for precise activation of Dicer1 mutations in Hic1+ mesenchymal stromal cells. This model resulted in the development of renal tumors closely mirroring human DICER1 sarcoma histologically and molecularly. Single-cell transcriptomics coupled with targeted spatial gene expression analysis revealed a Hic1+ progenitor population marked by Pdgfra, Dpt, and Mfap4, corresponding to universal fibroblasts of steady-state kidneys. These fibroblastic progenitors exhibit the capacity to undergo rhabdomyoblastic differentiation or transition to highly proliferative anaplastic sarcoma. Investigation of patient samples identified analogous cell states. This study uncovers a fibroblastic origin for DICER1 sarcoma and provides a faithful model for mechanistic investigation and therapeutic development for tumors within the rhabdomyosarcoma spectrum.