RET-driven osteoprotegerin expression links medullary thyroid cancer to osteoblastic bone metastases.

Development of bone metastases increases mortality in patients with medullary thyroid cancer (MTC), with ∼50% survival at 5 years after diagnosis, but the underlying mechanisms of action are unknown. We show that patient-derived MTC cells (RETC634W mutant TT and RETM918T mutant MZCRC1 cells) promote osteoblastic phenotypes due to reduced osteoclastic bone resorption. Mechanistically, activated RET increases osteoprotegerin (OPG) expression, an inhibitor of bone resorption, leading to decreased osteoclast differentiation. Furthermore, RET knockdown or pharmacological RET inhibition attenuates tumor burden and osteoblastic lesions in MTC-bearing mouse femurs. Circulating levels of OPG in humans increase in the plasma of patients with MTC and MTC bone metastases, and these levels are associated with poor overall survival. Patients who receive multi-kinase inhibitors have lower circulating OPG levels. These findings reveal a potential link between RET signaling and aberrant osteoblastic bone formation during tumor metastasis and suggest OPG as a potential biomarker for MTC bone metastases.