Project Details
Projekt
The impact of hypoxia pathway proteins in bone marrow niche cells during metastasis homing to bone
Subject Area
Hematology, Oncology
Term
since 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 401159467
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.
DFG Programme
Priority Programmes
