Title: A novel mouse model of testicular granulosa cell tumors PROJECT SUMMARY Despite the relatively high 5-year survival rate of granulosa cell tumors (GCTs) in stage I patients, poor prognosis is associated with patients at advanced tumor stage, justifying the need to study this type of poorly defined tumors. Of note, GCTs may also arise from the testis with low incidence. Thus, animal models are useful to investigate the pathogenesis of this disease. Overactivation of transforming growth factor ? (TGF?) receptor 1 (TGFBR1) using Amhr2-Cre to target mouse granulosa cells provokes the development of ovarian GCTs. It was found that male mice develop testicular GCTs at an early age. The exciting phenotypic manifestation of GCTs in the testes of these mice raised the question of how dysregulated TGF? signaling promotes testicular GCT formation. The central hypothesis is that dysregulation of TGF? signaling alters the differentiation program of Sertoli cells, promoting the transdifferentiation of Sertoli cell to malignant granulosa cells characteristic of GCTs. This hypothesis is based on compelling genetic evidence, and will be tested in a single aim by identifying mechanistic underpinnings of testicular GCT development resulting from constitutive activation of TGFBR1. A comprehensive approach combining transcriptomic and proteomic analyses will be utilized to address the posed question. Results of this application are expected to provide a paradigm shift for understanding gonadal tumorigenesis and reveal a novel link among growth factor signaling, cell fate alteration, and oncogenesis. Therefore, completion of this proposal will have a significant impact on the etiology of testicular GCTs. The findings have potential diagnostic and therapeutic value for sex cord-stromal tumors.
Our proposed studies to defining the role of TGF? signaling in testicular granulosa cell tumors is relevant to the mission of NCI. Our proposal will open new avenues for designing novel diagnostic and therapeutic interventions for a class of poorly defined tumors.