Tilman Rachner Group
Metabolic and signalling pathways as targets for personalized cancer therapies in breast and prostate cancer
Signalling pathways control cell and tissue growth during development and regeneration. One of these critical pathways is Wnt signalling, which is particularly involved in bone remodelling and skeletal homeostasis. Mutations and hyperactivation of Wnt signalling proteins and regulators are implicated in tumorigenesis. Dickkopf-1 (DKK-1) is a secreted, negative regulator of WNT signalling and blocks the differentiation of bone-building osteoblasts. High levels of DKK-1 are associated with osteolytic bone metastasis in multiple myeloma and breast cancer. However, additional effects of DKK-1 in cancer, apart from its role in bone biology, have been identified. These include the mediation of stress resistance mechanisms, modulations of cell cycle regulators, and the recruitment of tumor-promoting myeloid-derived suppressor cells into the tumor microenvironment.
Current research of our team explores the potential of DKK-1 as a target in personalized and precision therapy of human cancers. Using different approaches ranging from in vitro analyses to complex in vivo models and utilizing our close interaction with clinical work (biobanking, tissue samples etc), we assess the biological relevance of DKK-1 in malignant progression. These aspects include the investigation of the role of DKK-1 in tumor cell survival, signalling pathways, inflammation, stress and treatment resistance, as well as the metastasis to bone. In the past, we were able to demonstrate, that DKK-1 expression is increased in human breast cancer and can be targeted by blocking the mevalonate pathway using statins and amino-bisphosphonates. Moreover, we have shown that DKK-1 is regulated by p38 MAPKs in human prostate cancer cells and is a prognostic marker in clinical prostate cancer.
In addition, we have focussed our work on elucidating the potential of the mevalonate pathway as a therapeutic target in breast and prostate cancer by investigating the effects of statins and amino-bisphosphonates on tumor cell vitality, apoptosis and signalling pathways. In this regard, we currently identified one statin resistance mechanism in human breast cancer cells. Having access to a number of different, well established serum cohorts within our extensive biobank we are also assessing proteins for their potential as prognostic biomarkers in a range of malignancies. In this field, we published several studies on novel prognostic markers in bone-seeking malignancies and on the effects of endocrine therapies, such as tamoxifen, on important players in bone homeostasis, including DKK-1.
Future Projects and Goals
- Identify breast cancer patient subpopulations that would mostly benefit from an anti-DKK-1 targeted therapy
- Evaluating the potential link between DKK-1, tumor cell metabolism and glutamine dependence in cancer
- Assessing the role of DKK-1 in endocrine resistance of prostate cancer cells
Methodological and Technical Expertise
- Mouse models of cancer
- Mouse models of bone metastases
- Bone analyses incl. µCT