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

骨细胞是骨组织中最常见的细胞类型。它们生活在凹陷中，突出部分的面积约为1200平方米。通过这个错综复杂的网络，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沟通来调节骨矿物质的动态平衡。最近的研究表明，前列腺癌改变了骨的成分，材料的硬度是转移过程中的一个重要因素。然而，关于转移实体骨骼中骨细胞-陷窝网络的特征以及这如何影响肿瘤细胞的行为，人们知之甚少。中心假说是骨细胞网络和功能受到骨转移的影响，这些改变导致病理性的骨细胞活动和由此导致的骨脆性。为了验证这一假说，我们将(I)利用2D/3D成像/显微分析来表征骨转移形成过程中的骨细胞网络、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通讯以及其中的机械感觉作用，以及(Iv)分析原始骨细胞和肿瘤诱导的骨细胞的黏附分子谱，以确定调节骨细胞-肿瘤细胞相互作用的靶点。关键的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组织检查中得到验证。该项目将对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.