Abstract
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.
Competing Interest Statement
The authors have declared no competing interest.
