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

骨细胞是骨中最常见的细胞类型。它们的突起位于凹穴中，面积约为1200平方米。在这个复杂的网络中，骨细胞协调骨骼对机械刺激的适应，并通过与成骨细胞和破骨细胞的密切交流来调节骨矿物质的稳态。最近的研究表明，前列腺癌改变了骨成分，材料硬度是转移过程的重要因素。然而，对于骨转移实体骨中骨细胞腔隙网络的特征以及它如何影响肿瘤细胞的行为知之甚少。核心假设是骨细胞网络和功能受到骨骼转移的影响，这些改变有助于病理骨细胞的行为和由此产生的骨脆性。为了验证这一假设，我们将(I)在骨转移形成过程中使用2D/3D成像/显微分析表征骨细胞网络、局部力学特性和骨超微结构，（II）确定骨细胞功能对骨转移过程的影响，（III）评估骨细胞和肿瘤细胞之间的双向交流以及机械感觉在体外的作用。（IV）分析naïve骨细胞和肿瘤引发骨细胞的粘附分子谱，以确定调节骨细胞-肿瘤细胞相互作用的靶点。主要发现将在使用汉堡骨登记的乳腺癌和前列腺癌患者的骨转移活检中得到验证。该项目将为骨细胞和肿瘤细胞之间的相互作用提供新的和详细的见解，并可能提供新的治疗策略，通过调节骨细胞/肿瘤细胞的相互作用来抑制骨转移的形成。

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.