Platelet Gαz Regulates Ovarian Tumor Growth and Mediates the Effects of Chronic Stress

María Guadalupe Torres Carrizalez, BA (Advisor: Vahid Afshar-Kharghan, MD)

      Ovarian cancer is the most aggressive gynecologic cancer, with 12,450 estimated deaths in 2026. Elevated platelet counts are commonly observed in patients with ovarian cancer and are associated with enhanced tumor growth and poor prognosis. Patients with ovarian cancer are frequently exposed to elevated levels of stress, which has been correlated with accelerated disease progression and increased mortality. Interestingly, the platelet Gαz protein is activated by epinephrine through the α2A-adrenergic receptor, suggesting a potential mechanistic link between stress signaling and platelet-driven tumor progression. To investigate this, I evaluated the role of platelet Gαz in ovarian cancer using control (Gz^fl/fl) and platelet-specific Gαz knockout (Gz^D/D) mice. Gz^D/D mice exhibited a significant reduction in tumor growth compared to controls, indicating a pro-tumorigenic role for platelet Gαz signaling. Following this, I exposed Gz^fl/fl and Gz^D/D tumor-bearing mice to established stress protocols, which revealed that chronic stress significantly amplified the difference in tumor growth between Gz^fl/fl and Gz^D/D mice. Lastly, behavioral tests revealed hypersociability under chronic stress in both genotypes. Synaptic plasticity was also assessed by immunoblotting, revealing elevated levels of the synaptic marker PSD95, particularly in the hippocampus, in stressed mice. Collectively, these findings demonstrate that chronic stress exerts a pro-tumorigenic effect in ovarian cancer, at least partly by modulating platelet function through the Gαz signaling. Ultimately, this thesis constitutes a novel approach to understanding the bidirectional interaction between ovarian cancer and the brain that impacts tumor growth and social behavior. By elucidating the underlying mechanistic pathways, it aims to identify new therapeutic targets to improve not only tumor growth but also the quality of life in patients experiencing high levels of chronic stress.

Advisory Committee:

• Vahid Afshar-Kharghan, MD, Chair
• Peter Grace, PhD
• Amir Jazaeri, MD
• Anilkumar Pillai, PhD
• Anil Sood, MD

Join via Zoom (Please contact Ms. Torres Carrizalez for her Zoom meeting info.)