Project Details
Projekt
Dickkopf-1 as a critical determinant of malignant bone disease
Applicants
Dr. Tilmann Rachner; Professorin Dr. Martina Rauner
Subject Area
Hematology, Oncology
Term
from 2014 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 179902948
Metastatic bone disease remains a clinically relevant complication of many malignancies including those of breast, prostate and skin. In addition to enhanced osteoclastic bone resorption, impaired osteoblast function may also contribute to metastatic lesions. Dickkopf-1 (DKK-1) is a Wnt inhibitor and associated with the development of bone lesions in multiple myeloma by inhibiting osteoblast function. We have previously shown that DKK-1 is highly expressed in breast cancer tissue and elevated in the serum of affected patients. As part of a physician-scientist (Gerok) project, we identified elevated DKK-1 expression in prostate cancer tissue and significantly better survival in patients with prostate cancer, who had low levels of DKK-1 at the time of diagnosis. In vitro, breast and prostate cancer cell lines with high levels of DKK-1 inhibit osteoblast differentiation, which can be reversed by blocking DKK-1. Based on these results, we hypothesize that DKK-1 is a critical determinant of the formation of skeletal metastases and is a suitable prognostic marker for breast cancer survival and a potential therapeutic target in osteotropic malignancies. Our specific aims for the second funding period are to: (I) assess the prognostic value of DKK-1 using a prognostic breast cancer tissue array (from the NCI) and serum analyses of a well-characterized cohort of breast cancer patients; (II) analyze the role of DKK-1 in the mutual interaction of cancer and bone cells (MSC, osteoclasts) in vitro by modulating DKK-1 using RNAi and overexpression constructs; (III) determine the therapeutic potential of DKK-1 in murine models of breast cancer (subcutaneous, intratibial and intracardiac tumor models) by stably over-expressing and inhibiting DKK-1 in breast cancer and melanoma cell lines, and by inhibiting DKK-1 using a monoclonal antibody; (IV) clarify the role of non-tumor derived DKK-1 in cancer progression using mice with a conditional global deletion of DKK-1 after skeletal development or a deletion of DKK-1 specifically in osteoblasts. Tumor growth and bone destruction will be determined using micro-CT, luminescence imaging, and histology. Furthermore the bone anabolic effects of DKK-1 inhibition will be comprehensively studied using bone histomorphometry, serum bone remodeling markers and imaging. These studies will help to clarify the molecular mechanisms and therapeutic potential of modifying DKK-1 signaling in bone metastasis.
DFG Programme
Research Units
