Role of Dickkopf-1 as a mediator of inflammation in osteotropic cancers

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Dickkopf-1 (DKK-1) is an inhibitor of Wnt-signaling and best known as a key regulator of osteoblastic differentiation. In osteotropic malignancies, such as breast and prostate cancer, DKK-1 levels are increased, associated with the occurrence of bone metastases and, in some cases, linked to a poor prognosis. In recent years, DKK-1 has attained increasing attention as an important factor in tumor biology, which, in addition to its well-established effects on osteoblasts, may also mediate Wnt-independent mechanisms and interact with distinct signaling pathways.In the first funding period of µBone, we observed that a genetic knockdown of DKK-1 but not extracellular neutralization leads to a suppression of proinflammatory cytokines such as IL-1β, CXCL8, and CXCL1 as well as inhibited migration of the osteotropic prostate cancer cell line PC3. Consistently, subcellular fractioning of proteins revealed a predominant presence of DKK-1 in the nucleus and associated membranes. Given the key importance of inflammation in bone metastases, these data point towards the identification of a novel link between DKK-1 and inflammation as a new potential therapeutic target. Our project for the second µBone funding period aims at identifying the contribution of DKK-1 as a mediator of a proinflammatory response to early and late stages of bone metastases and if and how it sustains the dialogue between local cell types within the tumor microenvironment such as tumor cells, osteoblasts, and myeloid cells required for metastatic development. To address this question we will apply a comprehensive panel of methods comprising genetic and pharmaceutical modulation of DKK-1 and inflammatory mediators in cell lines and primary cells to assess their bidirectional interaction. In addition, we will perform direct and indirect co-culture and migration assays upon varying treatments and combinations of the cell types. Zebrafish and mouse models including transgenic mouse lines with global and cell type-specific DKK-1 knockouts in osteoblasts and myeloid cells represent an additional central aspect of our investigations. Here, an extensive number of readouts including live imaging, FACS, ELISA, and histology will uncover different aspects of local and systemic mechanisms. Finally, clinical samples from patients with osteotropic malignancies will be used to assess local and systemic expression of DKK-1 and to investigate potential correlations. These comprehensive analyzes will potentially reveal novel regulatory interactions between the immune system and DKK-1 and will therefore contribute to a detailed understanding if DKK-1 is suitable a therapeutic target in cancer metastasis to bone.