FOR 1586: SKELMET - Mesenchymal and Osteogenic Signalling Pathways in Malignant Bone Diseases
Final Report Abstract
Skeletal metastases develop in up to 90% of malignancies and frequently cause pathological fractures and severe pain. The intricacy of the underlying molecular pathogenesis remains a key challenge in treatment of skeletal metastases. Within the SKELMET research consortium, we were able to combine the expertise of basic-science oriented researchers focusing on animal models and imaging technologies to further scrutinize the mesenchymal and osteogenic pathways of bone lesions. We aimed to dissect molecular mechanisms of tumor-mediated inhibition of bone regeneration and hematopoiesis as well as the signaling pathways underlying exaggerated bone formation in osteoblastic metastasis. Before tumor cells home to the osteohematopoietic niche they modify the niche and foster adhesion and tumor spread by inducing a permissive signature in bone and immune cells. Thereby tumor cells generate a tolerant microenvironment in the bone and impair blood and bone regeneration. During the two funding periods of SKELMET, we identified a panel of novel targets that are specifically regulated through tumor/bone contact. High tumor expression of the non-canonical Wnt molecule Wnt5a was found to be associated with a longer survival in prostate cancer patients. Inhibition of TRAIL receptor R2 expression was identified as a promising therapeutic strategy, leading to an effective impairment of breast cancer cells and the capability of forming skeletal metastases. Expression of DKK-1 was found to act as a negative prognostic predictor in hormone receptor negative breast cancer. Another identified target is the KISS1R that opened a new opportunity for early diagnosis of myeloma bone disease. Furthermore Ebf2-expressing myeloma cells were able to support malignant hematopoietic cells. High JAM-A expression levels correlated with a negative disease outcome in patients with myeloma. JAM-A was suggested to serve as a biomarker for multiple myeloma patients, and soluble JAM-A as a serum-based marker for clinical stratification. We also developed imaging procedures that were shown to have greater sensitivity for the detection of earlystage metastatic lesions compared to standard µCT measurements. Systematic and interactive joint research delivered a detailed knowledge of crucial steps involved in the bone metastasis process. Based on our results we were able to establish the new nationwide Priority Program µbone in 2018 that aims to generate new insights into the mechanisms of tumor cell colonisation to the bone marrow and the interactions of tumor cells with the bone microenvironment to identify novel therapeutic concepts for the treatment and/or prevention of bone metastases.
