High Grade Serous Carcinoma (HGSC) is among the most lethal cancers affecting women in the U.S. While most therapeutic approaches in HGSC have focused on malignant epithelial tumor cells and their genetic alterations, it is becoming increasingly clear that the tumor microenvironment plays an equally important role in tumor evolution. We now recognize that the microenvironment serves not only as a scaffold for tissue organization and integrity but also provides key biomechanical and molecular signals that can affect every aspect of tumor growth and biology – including proliferation, survival, metabolism, stem cell fate, and response to chemotherapy. The presence of cancer cells induces a reaction in the surrounding stromal cells similar to fibrosis after an injury. These reactions can also reduce therapeutic efficacy of chemotherapy by creating a barrier for drug transport, while providing a protective environment for cancer cells to repopulate after completion of treatment. Our goal is to demonstrate that anti-cancer therapies should target not only malignant cancer cells but also the microenvironment that fosters tumor growth and survival (stromal cells). Our team of experts, led by Dr. Beth Y. Karlan, will accomplish this through three closely integrated projects that will test the hypothesis that activated stroma helps to drive ovarian cancer growth by triggering and supporting proliferative and metabolic pathways in adjacent cancer cells. Project 1 will test if reprogramming the activated stroma can improve therapeutic efficacy and prevent tumor recurrence. Project 2 will investigate the stroma-induced changes in epithelial ovarian cancer cells that lead to recurrence and chemoresistance. Project 3 will explore the metabolic relationship between tumor cells and activated stroma. All Projects will be supported by a strong Core infrastructure, including preclinical cancer models, pathology, and bioinformatics. We believe that identification of additional molecular sites to target anti-cancer therapeutics could undermine tumor progression and lead to more successful patient outcomes. This project is a collaborative effort that should contribute greatly to the molecular understanding of therapeutically resistant ovarian cancer and translate into more effective interventions in the clinical setting.