Project Details
Projekt
Role of Wnt5a in the interactions of prostate cancer cells and the bone microenvironment.
Applicant
Professor Dr. Lorenz C. Hofbauer
Subject Area
Hematology, Oncology
Term
from 2014 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 179902948
Prostate cancer has a high propensity to home to bone and commonly forms osteosclerotic lesions. In the first funding period, we identified Wnt5a to be specifically expressed in primary samples of osteotropic prostate cancer cells and found that overexpression of Wnt5a induced apoptosis and inhibited proliferation in vitro and correspondingly inhibited subcutaneous and intratibial tumor growth and subsequent bone destruction. Congruently, a high tumor expression of Wnt5a was associated with a longer survival in a cohort of 397 prostate cancer patients. Based on these results and its known regulation of bone remodeling and immune reactions, we hypothesize that Wnt5a affects key steps of skeletal metastases and represents a therapeutic target in the treatment of prostate cancer and related bone metastases. To test our hypotheses we will address the following specific aims: (I) To determine the paracrine effects of bone marrow cell-derived Wnt5a on prostate cancer cell biology. Underlying mechanisms will be determined using RNAi and specific inhibitors. Conditional knock-out mice that lack Wnt5a will be used to determine migration and skeletal metastasis of murine prostate cancer cells. (II) To examine the paracrine effects of tumor-derived Wnt5a on bone cells in vitro and ex vivo using calvaria cultures. The potential of tumor-derived Wnt5a to form a pre-metastatic niche and to promote bone metastases will be investigated in mouse models using multimodal bone imaging. Further, correlations of Wnt5a with the presence and type of bone metastases will be validated using our established tissue microarray (TMA). (III) To assess the modulation of immune cell migration and function by tumor-derived Wnt5a in vitro and in vivo. These studies will help to clarify the contribution of Wnt5a in prostate cancer and bone metastasis and to define its suitability as a novel biomarker and potential drug target.
DFG Programme
Research Units
