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. Overall design: 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.