There are two types of GCTs with different etiologies; adult (AGCT) and juvenile (JGCT) GCTs. AGCTs are common in peri- and postmenopausal women whereas JGCTs develop in juvenile girls and young women. The 402C > G point mutation in FOXL2 gene, a key regulator of GC development, is found in >90% of AGCTs, suggesting that mutant FOXL2 is a contributing factor to the development of AGCTs. In contrast, there have been no identified genetic or environmental factors associated with JGCTs. One of the factors hindering the research on JGCTs is the absence of proper research models to study the process of tumor formation. Development of GCTs has been reported in some genetically engineered mouse models. However, the causative mutations of GCTs in these models, such as null mutations in Inh-α or double null mutations in Smad1 and Smad5, are not found in human GCTs. Thus, the etiology of GCTs in these models does not represent that of human GCTs. We have recently developed a mouse JGCT model in which GCTs that are free of genetic mutations occur bilaterally with 100% prevalence by 8 weeks of age. In our mouse model, GDF9-iCre induces oocyte-specific expression of constitutively active mutant phosphoinositide 3-kinase (PI3K)(1), and the oocytic expression of mutant PI3K induces transformation of GCs. While the expression of mutant PI3K in oocyte was essential for the transformation of GCs, resultant GCTs could grow in nude mice, independent of oocytes or expression of mutant PI3K. There results support a totally novel concept that an alteration in the local/systemic environment can induce GCTs without cell autonomous mutations in GCs. Most importantly, although transgene was not expressed, phosphorylation of AKT and ERK1/2 were up-regulated in the transplanted GCTs, indicating that irreversible alterations in intracellular signaling are involved in the transformation of GCs. Here we propose to identify the cellular and molecular alterations in GCs during tumorigenesis utilizing the novel mouse model. In order to exclusively focus on cell autonomous alterations, we will isolate GCs at different stages of tumor progression and compare their characteristics in vitro. Furthermore, we will compare the transcriptome between normal and transformed GCs. Completion of proposed project should significantly advance our knowledge in the pathogenesis of GCTs, and it may lead to the development of novel diagnostic markers or therapeutics for GCTs.
|Effective start/end date||6/1/15 → 5/31/16|
- Granulosa Cell Tumour Research Foundation (AGMT-6/17/15)