Funding tool: Basic research projects
Project-ID: LS18-010
Project start: 01. Dezember 2019
Project end: will follow
Runtime: 36 months / ongoing
Funding amount: € 299.900,00

Brief summary:

Despite unprecedented advances in breast cancer (BC) treatment strategies during the last decade, up to one third of patients relapse of which 70% develop bone metastases. Manipulating the bone microenvironment, the osteoblast (OB)- rich endosteal niche in particular, at early BC stages may prevent disease relapse, reduce the rate of bone metastases and thereby ultimately decrease patient mortality. However, biomarkers in BC patients at high-risk to develop bone metastases are currently unknown. In addition, effective strategies to prevent bone metastases are lacking.
Here, we propose to unravel the pathophysiologic role of the endosteal niche, OB lineage cells in particular, during early phases of bone metastasis in BC. Innovative in vitro models of OB differentiation will be generated, in order to ultimately identify: (1) reliable biomarkers that predict the risk of bone metastatic disease; and (2) novel bone modifying agents (BMAs), that prevent early bone metastatic events in BC. Based on results of this application biomarker- directed clinical studies with BMAs will be initiated.
Aim 1: A novel dynamic 3D model of the OB-rich endosteal bone metastatic niche in BC will be generated by using poly-?- caprolacton scaffolds loaded with mesenchymal cells in a RCCS™ bioreactor. OB differentiation will be assessed by morphological and functional analyses. In addition, OB-lineage cells will be characterized by gene expression and secretion of soluble markers. The impact of tumor cells on the structure and composition of the bone niche will be studied by adding BC cells of different metastatic potential.
Aim 2: Since the endosteal surface is the preferred seeding and thriving area for tumor cells in the bone, the supportive role of OB-lineage cells on BC cell migration, adhesion, proliferation and drug resistance will subsequently be studied by using functional assays, imaging studies and histological examinations. Screenings for soluble markers representative for OB- mediated effects on tumor cells will additionally be performed.
Aim 3: Understanding molecular mechanisms behind the early metastatic colonization of the bone is a pivotal step towards the development of preventive treatment strategies for BC patients at high risk of skeletal involvement. Conventional and investigative BMAs will therefore be tested for their ability to prevent bone metastases and to overcome OB- mediated BC cell migration, proliferation and drug resistance.

Keywords:
Bone niche, Cell biology, Signal Transduction, Genomics, Proteomics