Principal Investigator: Robert Weiss

DESCRIPTION (provided by applicant): 

Type II testicular germ cell tumors (TGCTs) are the most common solid tumors in young men from 15-40 years of age and arise from developmentally arrested primordial germ cells. We previously created the only genetically engineered mouse model featuring malignant, metastatic TGCTs (the gPAK model) and showed that it recapitulates several of the key features of TGCTs, including their in utero origins and their exquisite sensitivity to conventional genotoxic chemotherapeutics. A major recent development in the field of human TGCTs is the finding that pluripotency-associated miRNAs of the miR371-373 cluster are highly expressed and secreted by malignant TGCTs, making measurement of serum abundance of miR371 a highly sensitive and specific clinical biomarker for TGCTs that is approaching clinical implementation. Despite widespread acceptance of miR371 as an accurate serum biomarker of TGCTs and awareness that miR371 and related microRNAs control genes involved in cell proliferation, survival, and pluripotency, virtually nothing is known about the roles of pluripotency associated miRNAs in TGCT pathogenesis. We recently used the gPAK mouse TGCT model, in which mice develop mixed germ cell tumors containing embryonal carcinoma (EC) and teratoma, to show that miRNAs of the homologous mouse miR290-295 cluster are present in high levels in the serum of mice with TGCTs as compared to tumor-free controls. Additionally, cultures of mouse TGCT cells show that the miR290-295 cluster is significantly and specifically expressed by pluripotent EC cells. We hypothesize that miR290-295 is not only an effective marker of TGCT but also plays a role in TGCT initiation and progression by regulating genes that control cell proliferation, cell death and pluripotency. In the first aim, the role of miR290-295 in maintaining cancer and stem cell hallmarks will be determined in pluripotent EC cells in vitro. In the second aim, a miR290-295 conditional knockout allele will be generated and used to assess tumor initiation and TGCT progression in the absence of miR290-295 in vivo. Together, these studies will reveal the functional contributions of the miR290-295 cluster in the development of TGCTs and set the stage for future mechanistic studies of a poorly understood potential driver of an important human malignancy.