Lineage tracing of mutant granulosa cells reveals in vivo protective mechanisms that prevent granulosa cell tumorigenesis

In the current study, we combined a multi-fluorescent reporter mouse model with a conditional knockout mouse model, in which the tumor suppressor genes Pten and p27 were deleted in GCs, to perform cell lineage tracing of mutant GCs. We found that only 30% of ovaries with substantial mutant GCs developed into GCTs that derived from a single mutant GC. In-depth molecular analysis of the process of tumorigenesis demonstrated that up-regulation of immune evasion genes Cd24a and Cd47 led, in part, to the transition of mutant GCs to GCTs. Therefore, treatment with the Cd47 inhibitor RRX-001 was tested and found to efficiently suppress the growth of GCTs in vivo. To reveal key cellular components and pathways responsible for the single cell derivation of GCT, we collected mutant GCs from ovaries of PD23 DKO mice (MT-GCs) and GCT cells from four-month-old DKO females with tumors (GCTs). GCs from ovaries of PD23 control mice (WT-GCs) were used as normal controls. RNA-Seq was performed to analyze the transcriptomic gene expression profiles of those cells.