Spatial single cell transcriptomic analysis of a lineage-traceable mouse model of DICER1 Syndrome informs tumor developmental hierarchy [RNA-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+Dpt+Pi16+ fibroblastic progenitor population, corresponding to 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. Overall design: Hic1+ mesenchymal cells were obtained from Hic1CreERT2/CreERT2:Rosa26LSL-tdTomato and Hic1CreERT2/CreERT2:Dicerfl/fl-D1693N;Rosa26LSL-tdTomato GEMM mice 4 weeks post tamoxifen treatment, which occurred when mice were 3-weeks-old. Following collection, cells were enriched for tdTomato+ cells via FACS. The resulting cell populations were grown in either Mesencult media or DMEM/F12 media with 10% FBS. Passaged cells were isolated and examined via bulk RNA-seq.