Molecular mechanisms of inhibition of bone regeration by myeloma cells via conditioning protected stem cell niches

点击翻译按钮获取中文摘要

Recent findings indicate an inhibition of bone regeneration and osteogenic programs by tumor cells during the metastatic process. We will test the hypothesis whether the reciprocal conditioning of mesenchymal precursors, its stem cell niches, and tumor cells modulates the function of mesenchymal stem cells (MSC) via mechanisms that consecutively inhibit bone regeneration and haematopoiesis. Based on our experience with MSC and solid databases of healthy cells we will address the interaction of osteogenic cells with myeloma cells and define candidate genes that are important in this cellular interaction. Humoral interactions between MSC and myeloma cells as well as cell-cell interactions will be analyzed using co-cultures of human cell lines. We intend to analyze changes in global gene expression patterns and to evaluate findings in cells from mouse models within the consortium. Lead candidates will be verified in human primary co-cultures. In order to mimic the comparison of a tumor niche with a normal niche, osteogenic cells cultured with myeloma cells will be compared to a coculture with CD34+ hematopoietic cells. We aim to identify key genes important for the modulation of stemness, redifferentiation and the inhibition of morphogenesis. This should contribute to the identification of novel targets in the metastatic process that interfere with regeneration principles and are involved in the induction of a protected stem cell status for tumor cells.