BioE Seminar Series: Role of Osteocytes in Regulation of Breast Cancer Bone Metastasis

Breast cancer patients with bone metastasis are at high-risk of painful or even fatal fractures due to their osteolytic lesions. Besides bisphosphonates (the standard adjuvant care), non-pharmaceutical intervention like exercise is commonly prescribed owing to its overall health benefits. Exercise, however, is challenging for many patients because of fear from activity related fracture, associated metabolic conditions such as obesity, and fatigue experienced during cancer treatments. High-frequency low-magnitude vibration (> 15 Hz, < 1 g) has been promoted as an easy-to-perform exercise alternative. Clinical trials and animal model studies on osteoporotic and cancer patients have confirmed the safety of vibration therapies, but the effect sizes declined in postmenopausal and/or obese subjects. To boost the skeletal benefits of vibration in postmenopausal and obese breast cancer patients, we propose a new strategy of enhancing bone responses to vibration using Yoda1-a highly selective agonist of Piezo1 cation channels. Piezo1 ion channels are the most abundantly expressed mechano-sensitive channels in osteocytes, the primary sensing cells in bone. We hypothesize that Yoda1-augmented vibration acts through the activation of Piezo1 and mechanotransduction pathways in osteocytes, which regulate the cross-talk among bone and cancer cells. Using a novel bone-on-chip platform that recapitulates the multi-cellular bone microenvironment, we demonstrated that i) Yoda1 enhanced the anabolic responses of osteocytes to vibration, and Yoda1 inhibited the growth and migration of breast cancer cells in vitro ii) combining Yoda1 and vibration led to enhanced effects on osteocytes and osteoclasts.