ELUCIDATING THE ROLE OF PIEZO2 MECHANOSENSORY NEURONS IN BONE PATHOLOGY DURING MALIGNANCY

Mechanotransduction, the process by which mechanical cues are converted into biochemical signals, is fundamental to bone homeostasis. In cancer-induced bone pathology, this process becomes strikingly evident: as tumors metastasize to the bone, patients suffer mechanical allodynia—intense pain elicited by even the slightest mechanical stimulus. Despite advances in orthopedic research, the molecular basis of this painful phenomenon remains poorly understood. Identifying the sensory pathways that mediate these pain signals is essential for devising new analgesics for cancer patients. PIEZO2, as the principal mechanically activated ion channel in sensory neurons, serves as an ideal molecular tool to investigate the role of neural mechanotransduction in bone cancer. We characterized PIEZO2-expressing mechanosensory neurons within the bone marrow microenvironment. We found that their activities in nociceptive nerves are enhanced by the presence of metastatic bone cancer. Further, our results showed that PIEZO2 sensory neuron activity in metastatic bone cancer is important for mechanical pain, highlighting the potential of targeting PIEZO2 for managing bone pain. Surprisingly, we show that PIEZO2 activity regulates tumor growth in the bone, providing us with unique opportunity to unravel neural pathways that mediate tumor microenvironment through mechanosensation. The outcome of our research can help control cancer pain, as well as redefine tumor microenvironment by elucidating how mechanosensory neurons, rather than just chemosensory pathways, interact with and regulate bone cancer malignancy.