Characterization of the impact of bone-seeking tumors on the osteocyte network and the osteocyte-mediated regulation of bone turnover

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Osteocytes are the most frequent cell type in bone. Residing in lacunae, their protrusions span an area of about 1200 m². With this intricate network, osteocytes orchestrate skeletal adaptation to mechanical stimuli and regulate bone mineral homeostasis through intense communication with osteoblasts and osteoclasts. Recent studies indicate that the bone composition is altered by prostate cancer and that material stiffness is an important factor for the metastatic process. However, little is known about the characteristics of the osteocyte-lacunar network in bone of metastatic entities and how this affects tumor cell behavior. The central hypothesis is that the osteocyte network and functionality are affected by skeletal metastasis and these alterations contribute to pathological bone cell actions and the resulting bone fragility. To test this hypothesis, we will (I) characterize the osteocyte network, local mechanical properties, and bone ultrastructure using 2D/3D imaging/microanalysis during bone metastases formation, (II) determine the impact of osteocyte functionality on the bone metastatic process, (III) assess the bidirectional communication between osteocytes and tumor cells and the role of mechanosensation therein in vitro, and (IV) analyze the adhesion molecule profile of naïve osteocytes and tumor-primed osteocytes to identify targets to modulate osteocyte-tumor cell interactions. Key findings will be validated in bone metastases biopsies obtained from breast- and prostate cancer patients using the Hamburg bone registry. This project will provide novel and detailed insights into the interaction between osteocytes and tumor cells and may provide new therapeutic strategies to inhibit the formation of bone metastases via modulation of osteocyte/tumor cell cross-talks.