A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development
Sex cord-stromal tumors account for approximately 8% of all ovarian cancers. These tumors are derived from the stromal compartment of the ovary instead of epithelial cells, from which the majority of ovarian cancers arise. The etiology of sex cord-stromal tumors is poorly defined, partially because research efforts in the field have been predominantly focused on ovarian cancers of epithelial cell origin. Lack of this knowledge prevents effective treatment for these tumors in the clinical setting. Thus, it is a critical problem to understand the mechanisms underlying the initiation and progression of ovarian sex cord-stromal tumors.Transgenic mouse models are among the most powerful tools for cancer research. The available models for sex cord-stromal tumors focus on abnormal changes in cancer cells or precursor cells. Emerging evidence highlights the importance of a cancer microenvironment in tumorigenesis. Notably, within the follicular microenvironment where sex cord-stromal tumors arise, oocytes drive folliculogenesis partially through transforming growth factor-beta (TGF-beta) superfamily members. However, little is known as to whether oocytes are involved in ovarian cancer development. To answer this question, we created a mouse model containing a constitutively active TGF-beta type 1 receptor (TGFBR1) specifically in the oocyte. Remarkably, these mice developed ovarian malignancies reminiscent of sex cord-stromal tumors.Our long-term goal is to define how ovarian cancers initiate and develop and utilize this knowledge to develop new diagnostic and therapeutic options to effectively prevent and treat ovarian cancers. The overall objective for this proposal is to define the contribution of overactivated TGF-beta signaling in the oocyte to ovarian cancer development and the underlying mechanisms of sex cord-stromal tumor formation. Our central hypothesis is that constitutive activation of TGF-beta signaling in the oocyte promotes granulosa cell tumor development via dysregulation of oocyte paracrine signaling and alterations of the transcriptome landscape of oocytes and granulosa cells.We will test our hypothesis by the following two aims:Specific Aim 1: Define the oncogenic role of constitutively active TGFBR1 in the oocyte. Using this newly established mouse model, we will identify the effect of constitutive activation of TGFBR1 in the oocyte on early folliculogenesis, apoptosis, and granulosa cell transformation, and deconstruct the role of oocyte TGF-beta signaling in granulosa cell tumor development. We will undertake an approach combining histological, cellular, and molecular assays to accomplish this aim. Specific Aim 2: Identify the oncogenic insult of sustained activation of TGF-beta signaling in the oocyte. We will explore the stage-specific function of constitutively active TGFBR1 in the oocyte by creating a complementary mouse model using zona pellucida 3 (Zp3)-Cre. The novel regulatory mechanisms underlying uncontrolled granulosa cell proliferation will be identified by analyzing the transcriptome landscape of oocytes and granulosa cells.Our proposal is novel because this is the first mouse model of sex cord-stromal tumors driven by transgenic activation of a known signaling cascade in neighboring cells instead of the cancer cells or precursor cells. Dysregulation of oocyte TGF-beta signaling may represent an early event prior to the formation of precursor/cancer cells. Thus, completion of the proposed studies will shed new light on the pathogenesis of ovarian sex cord-stromal tumors, and identify novel targets for their early detection and treatment. Consequently, our proposal is aligned well with the mission of Ovarian Cancer Research Program (OCRP). This application fits in with two priority research areas of OCRP, which are to understand cancer microenvironment and pathogenesis/progression and validate models to study ovarian cancer initiation/progression.Military Service members and their families suffer more emotional and physical burden from the ovarian cancer, a leading cause of death in women. By identifying novel targets for early detection and treatment of ovarian cancers, our proposed studies are expected to have a positive impact on the health and welfare of Military Service members and their families.