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The ovarian tumor microenvironment plays a critical yet is poorly understood role in the regulation of cancer cell behaviors including proliferation, migration, and response to chemotherapy treatments. Ovarian cancer is the deadliest gynecological cancer, due to diagnosis at late stages of the disease and increased resistance to chemotherapies for recurrent disease. Understanding how the tumor microenvironment (TME) interacts with biomechanical forces to drive changes to ovarian cancer cell behaviors could elucidate novel treatment strategies for this patient population. Additionally, limitations in current preclinical models of the ovarian TME do not permit investigation of crosstalk between signaling pathways and mechanical forces. Our study focused on uncovering how strains and hyaluronic acid (HA) interact to signal through the CD44 receptor to alter ovarian cancer cell growth, migration, and response to a commonly used chemotherapy, paclitaxel. Using an advanced 3D in vitro model, we were able to identify how interactions of strain and HA as in the TME synergistically drive enhanced proliferation and migration in an ovarian tumor model line, while decreasing response to paclitaxel treatment. This study demonstrates the importance of elucidating how the mechanical forces present in the ovarian TME drive disease progression and response to treatment.