The impact of hypoxia pathway proteins in bone marrow niche cells during metastasis homing to bone

我们体内的所有细胞都需要足够的氧压才能正常运作。因此，供氧不足(缺氧)是各种生理和病理条件下的突出特征，包括骨代谢、肿瘤发生和转移。缺氧过程中的中枢调节因子是低氧诱导因子(HIF)、受氧依赖的HIF脯氨酸羟基酶(PhDS)严格调控的转录因子，以及各种生物过程的驱动因子。在第一个资助期，我们揭示了骨髓内皮细胞中的PHD2-HIF2-VCAM1轴对于乳腺癌细胞向骨的归巢是必不可少的，成骨细胞及其前体细胞中的PHD2-HIF2-EPO/EPOR轴直接调节骨代谢，影响转移瘤细胞的生长。此外，针对SPP2084，我们最近扩大了我们独特的低氧途径蛋白转基因小鼠品系的收集，以更仔细地询问周细胞和成熟成骨细胞/骨髓脂肪细胞的作用。在一组初步的骨转移实验中，我们确定了新的表型，强调了它们在肿瘤细胞归巢到骨中的作用。因此，在这个新的项目提案中，我们已经做好了充分的准备，以进一步揭示PHD-HIF轴及其下游机制在骨转移瘤细胞归巢和生长过程中的影响。总之，我们相信，通过这个项目，我们将进一步深入了解HPPs在肿瘤细胞、骨血管和骨细胞之间相互作用中的作用，这可能会为阻断恶性串扰和改善骨转移的形成提供新的治疗策略。

All cells in our body require sufficient oxygen pressure to function properly. Therefore, insufficient oxygen supply (hypoxia) is a prominent feature in various physiological and pathological conditions, including bone metabolism, tumor development and metastasis. The central mediators during deprived oxygen are hypoxia inducible factors (HIF), transcription factors that are tightly regulated by oxygen-dependent HIF prolyl hydroxylases (PHDs), and drivers of various biological processes. During the first funding period, we revealed that the PHD2-HIF2-VCAM1 axis in bone marrow endothelial cells is essential for homing of breast carcinoma cells to the bone, and that PHD2-HIF2-Erythopoietin (EPO)/EPOR axis in osteoblasts and their progenitors directly regulates bone metabolism impacting growth of metastatic tumor cells. Furthermore, in view of SPP2084, we recently expanded our unique collection of hypoxia pathway protein transgenic mouse lines to more carefully interrogate the role of pericytes and mature osteoblasts/bone marrow adipocytes. In a set of preliminary bone metastasis experiments, we identified new phenotypes that underscore their role in tumor cell homing to bone. Within this new project proposal, we are therefore well equipped to further unravel the impact of the PHD-HIF axis and its downstream mechanisms during homing and growth of disseminated tumor cells in bone. Taken together, we are convinced that with this project we will provide further insights into the role of HPPs in the interaction between tumor cells, bone vasculature and bone cells that may provide new therapeutic strategies to interrupt the malignant crosstalk and ameliorate the formation of bone metastases.