Investigating the role of osteocyte steatosis as underlying mechanisms of the impaired osteocyte network due to bone metastasis

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Osteocytes are the most frequent cell type in bone and are highly interconnected via their lacunar-canalicular network (LCN). Via this communication tool, they orchestrate skeletal adaptation to mechanical stimuli and regulate bone turnover by communicating with osteoblasts and osteoclasts. Recent studies indicate a reciprocal interaction between osteocytes and tumor cells through the bone metastatic process, but little is known about the mechanisms of action and how this affects the response to mechanical loading. In the first funding period, we have identified osteocyte morphological signatures that are specific for osteosclerotic and osteolytic lesions in syngeneic mouse models of breast and prostate cancer bone metastasis models. These alterations, including reduced viability and connectivity, suggest an impaired ability for mechanosensation. Moreover, in vitro, we identified that the osteocyte-like MLO-Y4 cells undergo marked metabolic changes and acquire an adipogenic phenotype characterized by lipid accumulation after conditioning with RM1 prostate cancer cell supernatants. To that end, we have now formulated the hypothesis that due to lipid accumulation in osteocytes, i.e. osteocyte steatosis, mechanosensation via their LCN and communication with bone cells is impaired during bone metastasis conditions. To investigate this further, we defined three specific aims: (I) investigate the mechanism that leads to osteocyte steatosis after treatment with RM1 supernatants and characterize its impact on osteocyte function (i.e. mechanosensing and communication to osteoblasts and osteoclasts) in vitro, (II) visualize lipid droplets and other organelles related to fat metabolism (peroxisomes and mitochondria) in osteocytes and their LCN during prostate cancer bone metastasis and assess the impact of tumor cells on osteocyte response to mechanical loading in vivo, and III) validate key findings in biopsies from bone metastasis from patients with prostate cancer. This project will provide novel insights into the metabolic changes that osteocytes undergo upon tumor cell contact at unprecedented resolution and may deliver new molecular mechanisms that can be harnessed to interfere with the malignant crosstalk between the bone-central regulator osteocytes and tumor cells.